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Breast cancer is the most prevalent malignancy among women worldwide. Despite significant advances in treatment, it remains one of the leading causes of female mortality. The inability to effectively treat advanced and/or treatmentresistant breast cancer demonstrates the need to develop novel treatment strategies and targeted therapies. Centrosomes and their associated proteins have been shown to play key roles in the pathogenesis of breast cancer and thus represent promising targets for drug and biomarker development. Centrosomes are fundamental cellular structures in the mammalian cell that are responsible for error-free execution of cell division. Centrosome amplification and aberrant expression of its associated proteins such as Polo-like kinases (PLKs), Aurora kinases (AURKs) and Cyclin-dependent kinases (CDKs) have been observed in various cancers, including breast cancer. These aberrations in breast cancer are thought to cause improper chromosomal segregation during mitosis, leading to chromosomal instability and uncontrolled cell division, allowing cancer cells to acquire new genetic changes that result in evasion of cell death and the promotion of tumor formation. Various chemical compounds developed against PLKs and AURKs have shown meaningful antitumorigenic effects in breast cancer cells in vitro and in vivo. The mechanism of action of these inhibitors is likely related to exacerbation of numerical genomic instability, such as aneuploidy or polyploidy. Furthermore, growing evidence demonstrates enhanced antitumorigenic effects when inhibitors specific to centrosome-associated proteins are used in combination with either radiation or chemotherapy drugs in breast cancer. This review focuses on the current knowledge regarding the roles of centrosome and centrosome-associated proteins in breast cancer pathogenesis and their utility as novel targets for breast cancer treatment. [ABSTRACT FROM AUTHOR]

Background: Polo-like kinases (PLKs) are a kinase class of serine/threonine with five members that play crucial roles in cell cycle regulation. However, their biological functions, regulation, and expression remain unclear. This study revealed the molecular properties, oncogenic role, and clinical significance of PLK genes in pan-cancers, particularly in kidney renal papillary cell carcinoma (KIRP). Methods: We evaluated the mutation landscape, expression level, and prognostic values of PLK genes using bioinformatics analyses and explored the association between the expression level of PLK genes and tumor microenvironment (TME), immune subtype, cancer immunotherapy, tumor stemness, and drug sensitivity. Finally, we verified the prognostic value in patients with KIRP through univariate and multivariate analyses and nomogram construction. Results: PLK genes are extensively altered in pan-cancer, which may contribute to tumorigenesis. These genes are aberrantly expressed in some types of cancer, with PLK1 being overexpressed in 31 cancers. PLK expression is closely associated with the prognosis of various cancers. The expression level of PLK genes is related with sensitivity to diverse drugs and cancer immunity as well as cancer immunotherapy. Importantly, we verified that PLK1 was overexpressed in KIRP tissues and could be an unfavorable prognostic biomarker in patients with KIRP. Hence, PLK1 may serve as an oncogenic gene in KIRP and should be explored in future studies. Conclusions: Our study comprehensively reports the molecular characteristics and biological functions of PLK family gens across human cancers and recommends further investigation of these genes as potential biomarkers and therapeutic targets, especially in KIRP.

Background: In the realm of tumor-targeted therapeutics, Polo-like kinases (PLKs) are a significant group of protein kinases that were found recently as being related to tumors. However, the significance of PLKs in pan-cancer remains systematically studied. Methods and materials: We integrated multi-omics data to comprehensively investigate the expression patterns of the PLK family across various cancer types. Subsequently, study examined the associations between tumor mutation burden (TMB), microsatellite instability (MSI), immune subtype classification, immune infiltration, tumor microenvironment scores, immune checkpoint gene expression, and the PLKs expression profiles within various tumor types. Furthermore, using our mRNA sequencing data (TRUCE01) and four bladder cancer (BLCA) cohorts (GSE111636, GSE176307, and IMvigor210), We examined the correlation between the expression level of PLK and immunotherapy effectiveness. Next, Gene set enrichment analysis (GSEA) was evaluated to find that potentially enriched PLK signaling pathways. Utilizing TIMER 2.0, we conducted an immune infiltration analysis underlying transcriptome expression, copy number variations (CNV), or somatic mutations of PLKs in BLCA. Finally, mRNA expression validation of PLK1/3/4 by real-time PCR within 10 paired BLCA tissues, protein expression verification through the Human Protein Atlas (HPA), and PLK4 in vitro cytological studies have been employed in BLCA. Results: The expression of most of the PLK family members exhibits variation between cancerous tissues and adjacent normal tissues across various cancer species. Furthermore, the expression of PLKs demonstrates a significant association with immunotyping, infiltration of immune cell, tumor mutational burden (TMB), microsatellite instability (MSI), immunological checkpoint gene activity and therapeutic effectiveness in pan-tumor tissues. Additional investigation into the correlation between the PLK family and BLCA has revealed that the expression of the PLK genes holds substantial significance in the biological processes of BLCA. Furthermore, a notable association has been observed between the copy number variation, variant status, and the degree of certain immunological cell infiltration. Of note, the expression validation and in vitro phenotypic experiments have demonstrated that PLK4 has a significant function in promoting the BLCA cell proliferation, migration, and invasion. Conclusion: Collectively, based on various databases, our results highlight the involvement of PLK gene family in the formation of different types of tumors and identify PLK-related genes that may be used for therapy.

In most metazoans, centrioles are lost during oogenesis, ensuring that the zygote is endowed with the correct number of two centrioles, which are paternally contributed. How centriole architecture is dismantled during oogenesis is not understood. Here, we analyze with unprecedent detail the ultrastructural and molecular changes during oogenesis centriole elimination in Caenorhabditis elegans. Centriole elimination begins with loss of the so‐called central tube and organelle widening, followed by microtubule disassembly. The resulting cluster of centriolar proteins then disappears gradually, usually moving in a microtubule‐ and dynein‐dependent manner to the plasma membrane. Our analysis indicates that neither Polo‐like kinases nor the PCM, which modulate oogenesis centriole elimination in Drosophila, do so in C. elegans. Furthermore, we demonstrate that the central tube protein SAS‐1 normally departs initially from the organelle, which loses integrity earlier in sas‐1 mutants. Overall, our work provides novel mechanistic insights regarding the fundamental process of oogenesis centriole elimination. Synopsis: Paternal contribution of centrioles ensures centriole homeostasis in zygotes, but how maternal centrioles are lost in metazoans is unclear. Detailed ultrastructural analyses of centriole elimination during worm oogenesis show that departure of the central tube protein SAS‐1 marks the onset of organelle disassembly. Oogenesis centriole elimination in C. elegans occurs in two steps.Loss of ultrastructural integrity precedes clearance of centriolar protein cluster.Central tube removal and organelle widening mark the onset of centriole elimination.The central tube protein SAS‐1 is required for centriole stability during oogenesis. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer is a complex disease and the underlying molecular mechanisms driving cancer initiation and progression is crucial for the development of effective approaches for cancer management. Exploring the molecular landscape of cancer can shed light on novel biomarkers, therapeutic targets, and strategies for personalized medicine. In this study, we determined the potential involvement of PLK5 in multiple cancers employing cancer tissue microarrays (TMAs). We found a downregulation of PLK5 in these cancers. Further, using publicly available GTEx and TCGA databases, we validated our findings and extended our investigations to additional cancer types. Overall, our data suggested a potential tumor suppressor role for PLK5. The polo-like kinase (PLK) family of serine/threonine kinases contains five members (PLK1–5). Most PLKs are involved in cell cycle regulation and DNA damage response. However, PLK5 is different as it lacks a functional kinase domain and is not involved in cell cycle control. PLK5 remains the least-studied family member, and its role in oncogenesis remains enigmatic. Here, we identified tissues with high PLK5 expression by leveraging the Protein Atlas and GTEx databases with relevant literature and selected ovarian, lung, testis, endometrium, cervix, and fallopian tube tissues as candidates for further investigation. Subsequently, we performed immunohistochemical staining for PLK5 on multiple tissue microarrays followed by Vectra scanning and quantitative inForm analysis. This revealed consistently downregulated PLK5 expression in these cancers compared to normal tissues. To validate and extend our findings, we performed pan-cancer analysis of PLK5 expression using public RNAseq databases (TCGA and GTEx). We found PLK5 is downregulated in 18 cancer types, including our selected candidates. Interestingly, we also observed PLK5 expression remains consistently low in later stages of cancer, suggesting PLK5 may have a greater role in tumor initiation than cancer progression. Overall, our study demonstrates PLK5 downregulation in multiple cancers, highlighting its role as a tumor suppressor. [ABSTRACT FROM AUTHOR]

Maintaining a definite and stable pool of dividing stem cells plays an important role in organ development. This process requires an appropriate progression of mitosis for proper spindle orientation and polarity to ensure the ability of stem cells to proliferate and differentiate correctly. Polo-like kinases (Plks)/Polo are the highly conserved serine/threonine kinases involved in the initiation of mitosis as well as in the progression of the cell cycle. Although numerous studies have investigated the mitotic defects upon loss of Plks/Polo in cells, little is known about the in vivo consequences of stem cells with abnormal Polo activity in the context of tissue and organism development. The current study aimed to investigate this question using the Drosophila intestine, an organ dynamically maintained by the intestinal stem cells (ISCs). The results indicated that the polo depletion caused a reduction in the gut size due to a gradual decrease in the number of functional ISCs. Interestingly, the polo-deficient ISCs showed an extended G2/M phase and aneuploidy and were subsequently eliminated by premature differentiation into enterocytes (ECs). In contrast, the constitutively active Polo (poloT182D) suppressed ISC proliferation, induced abnormal accumulation of β-tubulin in cells, and drove ISC loss via apoptosis. Therefore, Polo activity should be properly maintained for optimal stem cell function. Further analysis suggested that polo was a direct target gene of Sox21a, a Sox transcription factor that critically regulates stem cell activity. Together, this study provided a novel perspective on the correlation between the progression of mitosis and the ISC function in Drosophila. [ABSTRACT FROM AUTHOR]

The polo-like kinase (PLK) family of serine/threonine kinases contains five members (PLK1–5). Most PLKs are involved in cell cycle regulation and DNA damage response. However, PLK5 is different as it lacks a functional kinase domain and is not involved in cell cycle control. PLK5 remains the least-studied family member, and its role in oncogenesis remains enigmatic. Here, we identified tissues with high PLK5 expression by leveraging the Protein Atlas and GTEx databases with relevant literature and selected ovarian, lung, testis, endometrium, cervix, and fallopian tube tissues as candidates for further investigation. Subsequently, we performed immunohistochemical staining for PLK5 on multiple tissue microarrays followed by Vectra scanning and quantitative inForm analysis. This revealed consistently downregulated PLK5 expression in these cancers compared to normal tissues. To validate and extend our findings, we performed pan-cancer analysis of PLK5 expression using public RNAseq databases (TCGA and GTEx). We found PLK5 is downregulated in 18 cancer types, including our selected candidates. Interestingly, we also observed PLK5 expression remains consistently low in later stages of cancer, suggesting PLK5 may have a greater role in tumor initiation than cancer progression. Overall, our study demonstrates PLK5 downregulation in multiple cancers, highlighting its role as a tumor suppressor.

Tumor immune microenvironment plays an important role in tumorigenesis and metastasis. Polo-like kinases 4 (PLK4) is a crucial regulatory factor in the process of cell cycle, and its abnormal regulation often leads to a variety of diseases including tumorigenesis. We have previously explored the function of PLK4 in sensitizing chemotherapy in glioma, but there are few studies on the correlation between PLK4 and tumor immune microenvironment. PLK4 was found to be highly expressed in various types of cancers, including glioma and closely related to histological and genetic features in public databases. Kaplan-Meier survival analysis and Cox regression analysis revealed that higher PLK4 expression is associated with poorer prognosis. GO and KEGG functional enrichment analysis showed that PLK4 expression level was significantly correlated with regulation of immune microenvironment, cell cycle and genomic instability. Immune infiltration analysis showed that high expression of PLK4 resulted in reduced infiltration of macrophages. M1 macrophage infiltration assays showed that PLK4 knockdown GBM cell lines promoted the recruitment of M1-type macrophages via altering expression of chemokines. And in intracranial tumor mouse models, PLK4 inhibition increased tumorinfiltrating M1 macrophages. In summary, our results demonstrated the correlation between high PLK4 expression level and malignant progression of gliomas, and the possible involvement of PLK4 in regulation of cell cycle, cell proliferation and macrophages infiltration in gliomas. [ABSTRACT FROM AUTHOR]

Introduction: Polo-like kinases (PLKs) have five isoforms, all of which play crucial roles in cell cycle and cell proliferation, offering opportunities for drug design and treatment of cancers and other related diseases. Notably, PLK1 and PLK4 have been extensively investigated as cancer drug targets. One distinctive feature of PLKs is the presence of a unique polo-box domain (PBD), which regulates kinase activity and subcellular localization. This provides possibilities for specifically targeting PLKs., Area Covered: This article provides an overview of the roles of PLKs in various cancers and related diseases, as well as the drug development involving PLKs, with a particular focus on PLK1 and PLK4. It summarizes the PLK1 and PLK4 inhibitors that have been disclosed in patents or literature (from 2018 - present), which were sourced from SciFinder and WIPO database., Expert Opinion: After two decades of drug development on PLKs, several drugs progressed into clinical trials for the treatment of many cancers; however, none of them has been approved yet. Further elucidating the mechanisms of PLKs and identifying and developing highly selective ATP-competitive inhibitors, highly potent drug-like PBD inhibitors, degraders, etc. may provide new opportunities for cancer therapy and the treatment for several nononcologic diseases. PLKs inhibition-based combination therapies can be another helpful strategy.

Background: Polo-like kinase 1 (PLK1) belongs to polo-like kinases family and affects cell cycles. However, the role of PLK1 in some malignant tumors remains unclear. Methods: To obtain a comprehensive view of PLK1 expression patterns, public databases including The Cancer Genome Atlas, Cancer Cell Line Encyclopedia, the Genotype-Tissue Expression, and human cell landscape databases were employed. The correlation of PLK1 expression with prognosis, immune infiltrations, immune checkpoint genes, tumor mutational burden (TMB), microsatellite instability (MSI), mismatch repair (MMR), and DNA methylation was examined. Besides, we validated the results of clear cell renal cell carcinoma (ccRCC) in two cohorts, with quantitative real-time PCR, Western blot, and loss-of-function experiments. Results: By mining public datasets, we discovered that PLK1 expression in tumor tissues and cancer cell lines displayed heterogeneity compared to normal controls across different cancers. Besides, high expression of PLK1 results in shorter survival time in 15 cancer types, especially in ccRCC. PLK1 expression showed strong association with immune cell infiltration and immune checkpoint genes across cancer types. Moreover, we identified a strong association between PLK1 expression and TMB, MSI MMR, and DNA methylation. PLK1 was validated to be highly expressed in ccRCC tissues and promote ccRCC cell proliferation, migration, invasion, and cell cycle. Mechanistically, PLK1 could regulate forkhead box protein M1 and target cell cycle-associated genes to participate in cell cycle control. Conclusion: PLK1 has important prognostic value and is associated with tumor immunity across cancer types including ccRCC. [ABSTRACT FROM AUTHOR]

The morula-to-blastocyst transition (MBT) culminates with formation of inner cell mass (ICM) and trophectoderm (TE) lineages. Recent studies identified signaling pathways driving lineage specification, but some features of these pathways display significant species divergence. To better understand evolutionary conservation of the MBT, we completed a meta-analysis of RNA sequencing data from five model species and ICMTE differences from four species. Although many genes change in expression during the MBT within any given species, the number of shared differentially expressed genes (DEGs) is comparatively small, and the number of shared ICMTE DEGs is even smaller. DEGs related to known lineage determining pathways (e.g., POU5F1) are seen, but the most prominent pathways and functions associated with shared DEGs or shared across individual species DEG lists impact basic physiological and metabolic activities, such as TCA cycle, unfolded protein response, oxidative phosphorylation, sirtuin signaling, mitotic roles of polo-like kinases, NRF2-mediated oxidative stress, estrogen receptor signaling, apoptosis, necrosis, lipid and fatty acid metabolism, cholesterol biosynthesis, endocytosis, AMPK signaling, homeostasis, transcription, and cell death. We also observed prominent differences in transcriptome regulation between ungulates and nonungulates, particularly for ICM- and TE-enhanced mRNAs. These results extend our understanding of shared mechanisms of the MBT and formation of the ICM and TE and should better inform the selection of model species for particular applications. [ABSTRACT FROM AUTHOR]

Background: Polo-like kinases (PLKs) are conserved serine/threonine kinases that regulate the cell cycle. To date, the role of Giardia lamblia PLK (GlPLK) in cells has not been studied. Here, we report our investigation on the function of GlPLK to provide insight into the role of this PKL in Giardia cell division, especially during cytokinesis and flagella formation. Methods: To assess the function of GIPLK, Giardia trophozoites were treated with the PLK-specific inhibitor GW843286X (GW). Using a putative open reading frame for the PLK identified in the Giardia genomic database, we generated a transgenic Giardia expressing hemagglutinin (HA)-tagged GlPLK and used this transgenic for immunofluorescence assays (IFAs). GlPLK expression was knocked down using an anti-glplk morpholino to observe its effect on the number of nuclei number and length of flagella. Giardia cells ectopically expressing truncated GlPLKs, kinase domain + linker (GlPLK-KDL) or polo-box domains (GlPLK-PBD) were constructed for IFAs. Mutant GlPLKs at Lys51, Thr179 and Thr183 were generated by site-directed mutagenesis and then used for the kinase assay. To elucidate the role of phosphorylated GlPLK, the phosphorylation residues were mutated and expressed in Giardia trophozoites Results: After incubating trophozoites with 5 μM GW, the percentage of cells with > 4 nuclei and longer caudal and anterior flagella increased. IFAs indicated that GlPLK was localized to basal bodies and flagella and was present at mitotic spindles in dividing cells. Morpholino-mediated GlPLK knockdown resulted in the same phenotypes as those observed in GW-treated cells. In contrast to Giardia expressing GlPLK-PBD, Giardia expressing GlPLK-KDL was defective in terms of GIPLK localization to mitotic spindles and had altered localization of the basal bodies in dividing cells. Kinase assays using mutant recombinant GlPLKs indicated that mutation at Lys51 or at both Thr179 and Thr183 resulted in loss of kinase activity. Giardia expressing these mutant GlPLKs also demonstrated defects in cell growth, cytokinesis and flagella formation. Conclusions: These data indicate that GlPLK plays a role in Giardia cell division, especially during cytokinesis, and that it is also involved in flagella formation. [ABSTRACT FROM AUTHOR]

Tazarotene-induced gene 1 (TIG1) is considered to be a tumor suppressor gene that is highly expressed in normal or well-differentiated colon tissues, while downregulation of TIG1 expression occurs in poorly differentiated colorectal cancer (CRC) tissues. However, it is still unclear how TIG1 regulates the tumorigenesis of CRC. Polo-like kinases (Plks) are believed to play an important role in regulating the cell cycle. The performance of PLK2 in CRC is negatively correlated with the differentiation status of CRC tissues. Here, we found that PLK2 can induce the growth of CRC cells and that TIG1 can prevent PLK2 from promoting the proliferation of CRC cells. We also found that the expression of PLK2 in CRC cells was associated with low levels of Fbxw7 protein and increased expression of cyclin E1. WhenTIG1 was coexpressed with PLK2, the changes in Fbxw7/cyclin E1 levels induced by PLK2 were reversed. In contrast, silencing TIG1 promoted the proliferation of CRC, and when PLK2 was also silenced, the proliferation of CRC cells induced by TIG1 silencing was significantly inhibited. The above research results suggest that TIG1 can regulate the tumorigenesis of CRC by regulating the activity of PLK2. [ABSTRACT FROM AUTHOR]

Background/Aim: Wild yam extract [Dioscorea villosa, (WYE)] is consistently lethal at low IC50s across diverse cancer-lines in vitro. Unlike traditional anti-cancer botanicals, WYE contains detergent saponins which reduce oil-water interfacial tensions causing disintegration of lipid membranes and causing cell lysis, creating an interfering variable. Here, we evaluate WYE at sub-lethal concentrations in MDA-MB-231 triple-negative breast cancer (TNBC) cells. Materials and Methods: Quantification of saponins, membrane potential, lytic death and sub-lethal WYE changes in whole transcriptomic (WT) mRNA, miRNAs and biological parameters were evaluated. Results: WYE caused 346 differentially expressed genes (DEGs) out of 48,226 transcripts tested; where up-regulated DEGS reflect immune stimulation, TNF signaling, COX2, cytokine release and cholesterol/steroid biosynthesis. Down-regulated DEGs reflect losses in cell division cycle (CDC), cyclins (CCN), cyclin-dependent kinases (CDKs), centromere proteins (CENP), kinesin family members (KIFs) and polo-like kinases (PLKs), which were in alignment with biological studies. Conclusion: Sub-lethal concentrations of WYE appear to evoke pro-inflammatory, steroid biosynthetic and cytostatic effects in TNBC cells. [ABSTRACT FROM AUTHOR]

Aim. This study is aimed at building a risk model based on the genes that significantly altered the proliferation of lung adenocarcinoma cells and exploring the underlying mechanisms. Methods. The data of 60 lung adenocarcinoma cell lines in the Cancer Dependency Map (Depmap) were used to identify the genes whose knockout led to dramatical acceleration or deacceleration of cell proliferation. Then, univariate Cox regression was performed using the survival data of 497 patients with lung adenocarcinoma in The Cancer Genome Atlas (TCGA). The least absolute shrinkage and selection operator (LASSO) model was used to construct a risk prediction score model. Patients with lung adenocarcinoma from TCGA were classified into high- or low-risk groups based on the scores. The differences in clinicopathologic, genomic, and immune characteristics between the two groups were analyzed. The prognosis of the genes in the model was verified with immunohistochemical staining in 100 samples from the Department of Thoracic Surgery, Zhongshan Hospital, and the alteration in the proliferation rate was checked after these genes were knocked down in lung adenocarcinoma cells (A549 and H358). Results. A total of 55 genes were found to be significantly related to survival by combined methods, which were crucial to tumor progression in functional enrichment analysis. A six-gene-based risk prediction score, including the proteasome subunit beta type-6 (PSMB6), the heat shock protein family A member 9 (HSPA9), the deoxyuridine triphosphatase (DUT), the cyclin-dependent kinase 7 (CDK7), the polo-like kinases 1 (PLK1), and the folate receptor beta 2 (FOLR2), was built using the LASSO method. The high-risk group classified with the score model was characterized by poor overall survival (OS), immune infiltration, and relatively higher mutation load. A total of 9864 differentially expressed genes and 138 differentially expressed miRNAs were found between the two groups. Also, a nomogram comparing score model, age, and the stage was built to predict OS for patients with lung adenocarcinoma. Using immunohistochemistry, the expression levels of PSMB6, HSPA9, DUT, CDK7, and PLK1 were found to be higher in lung adenocarcinoma tissues of patients, while the expression of FOLR2 was low, which was consistent with survival prediction. The knockdown of PSMB6 and HSPA9 by siRNA significantly downregulated the proliferation of A549 and H358 cells. Conclusion. The proposed score model may function as a promising risk prediction tool for patients with lung adenocarcinoma and provide insights into the molecular regulation mechanism of lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

Background: Polo-like kinases (PLKs) are a kinase class of serine/threonine with five members that play crucial roles in cell cycle regulation. However, their biological functions, regulation, and expression remain unclear. This study revealed the molecular properties, oncogenic role, and clinical significance of PLK genes in pan-cancers, particularly in kidney renal papillary cell carcinoma (KIRP)., Methods: We evaluated the mutation landscape, expression level, and prognostic values of PLK genes using bioinformatics analyses and explored the association between the expression level of PLK genes and tumor microenvironment (TME), immune subtype, cancer immunotherapy, tumor stemness, and drug sensitivity. Finally, we verified the prognostic value in patients with KIRP through univariate and multivariate analyses and nomogram construction., Results: PLK genes are extensively altered in pan-cancer, which may contribute to tumorigenesis. These genes are aberrantly expressed in some types of cancer, with PLK1 being overexpressed in 31 cancers. PLK expression is closely associated with the prognosis of various cancers. The expression level of PLK genes is related with sensitivity to diverse drugs and cancer immunity as well as cancer immunotherapy. Importantly, we verified that PLK1 was overexpressed in KIRP tissues and could be an unfavorable prognostic biomarker in patients with KIRP. Hence, PLK1 may serve as an oncogenic gene in KIRP and should be explored in future studies., Conclusions: Our study comprehensively reports the molecular characteristics and biological functions of PLK family gens across human cancers and recommends further investigation of these genes as potential biomarkers and therapeutic targets, especially in KIRP., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Proliferative chronic myelomonocytic leukemia (pCMML), an aggressive CMML subtype, is associated with dismal outcomes. RAS pathway mutations, mainly NRASG12D, define the pCMML phenotype as demonstrated by our exome sequencing, progenitor colony assays and a Vav-Cre-NrasG12D mouse model. Further, these mutations promote CMML transformation to acute myeloid leukemia. Using a multiomics platform and biochemical and molecular studies we show that in pCMML RAS pathway mutations are associated with a unique gene expression profile enriched in mitotic kinases such as polo-like kinase 1 (PLK1). PLK1 transcript levels are shown to be regulated by an unmutated lysine methyl-transferase (KMT2A) resulting in increased promoter monomethylation of lysine 4 of histone 3. Pharmacologic inhibition of PLK1 in RAS mutant patient-derived xenografts, demonstrates the utility of personalized biomarker-driven therapeutics in pCMML. Chronic myelomonocytic leukaemia is classified as proliferative (pCMML) or dysplastic based on the white blood cell counts but biological differences are unclear. Here, the authors show genetic, transcriptomic and epigenomic differences between these two subtypes establishing that pCMML is RAS-pathway driven and that inhibiting RAS-driven PLK1 expression is a viable therapeutic target. [ABSTRACT FROM AUTHOR]

Polo-like kinases (Plks) are critical regulatory molecules during the cell cycle process. This family has five members: Plk1, 2, 3, 4, and 5. Plk4 has been identified as a master regulator of centriole replication, and its aberrant expression is closely associated with cancer development. In this review, we depict the DNA, mRNA, and protein structure of Plk4, and the regulation of Plk4 at a molecular level. Then we list the downstream targets of Plk4 and the hallmarks of cancer associated with these targets. The role of Plk4 in different cancers is also summarized. Finally, we review the inhibitors that target Plk4 in the hope of discovering effective anticancer drugs. From authors' perspective, Plk4 might represent a valuable tumor biomarker and critical target for cancer diagnosis and therapy. [ABSTRACT FROM AUTHOR]

Background: Cancer stem-like cell is a key barrier for therapeutic resistance and metastasis in various cancers, including breast cancer, yet the underlying mechanisms are still elusive. Through a genome-wide lncRNA expression profiling, we identified that LINC00115 is robustly upregulated in chemoresistant breast cancer stem-like cells (BCSCs)., Methods: LncRNA microarray assay was performed to document abundance changes of lncRNAs in paclitaxel (PTX)-resistant MDA-MB-231 BCSC (ALDH + ) and non-BCSC (ALDH - ). RNA pull-down and RNA immunoprecipitation (RIP) assays were performed to determine the binding proteins of LINC00115. The clinical significance of the LINC00115 pathway was examined in TNBC metastatic lymph node tissues. The biological function of LINC00115 was investigated through gain- and loss-of-function studies. The molecular mechanism was explored through RNA sequencing, mass spectrometry, and the CRISPR/Cas9-knockout system. The therapeutic potential of LINC00115 was examined through xenograft animal models., Results: LINC00115 functions as a scaffold lncRNA to link SETDB1 and PLK3, leading to enhanced SETDB1 methylation of PLK3 at both K106 and K200 in drug-resistant BCSC. PLK3 methylation decreases PLK3 phosphorylation of HIF1α and thereby increases HIF1α stability. HIF1α, in turn, upregulates ALKBH5 to reduce m 6 A modification of LINC00115, resulting in attenuated degradation of YTHDF2-dependent m 6 A-modified RNA and enhanced LINC00115 stability. Thus, this positive feedback loop provokes BCSC phenotypes and enhances chemoresistance and metastasis in triple-negative breast cancer. SETDB1 inhibitor TTD-IN with LINC00115 ASO sensitizes PTX-resistant cell response to chemotherapy in a xenograft animal model. Correlative expression of LINC00115, methylation PLK3, SETDB1, and HIF1α are prognostic for clinical triple-negative breast cancers., Conclusions: Our findings uncover LINC00115 as a critical regulator of BCSC and highlight targeting LINC00115 and SETDB1 as a potential therapeutic strategy for chemotherapeutic resistant breast cancer., (© 2024. The Author(s).)

Background: In the realm of tumor-targeted therapeutics, Polo-like kinases (PLKs) are a significant group of protein kinases that were found recently as being related to tumors. However, the significance of PLKs in pan-cancer remains systematically studied., Methods and Materials: We integrated multi-omics data to comprehensively investigate the expression patterns of the PLK family across various cancer types. Subsequently, study examined the associations between tumor mutation burden (TMB), microsatellite instability (MSI), immune subtype classification, immune infiltration, tumor microenvironment scores, immune checkpoint gene expression, and the PLKs expression profiles within various tumor types. Furthermore, using our mRNA sequencing data (TRUCE01) and four bladder cancer (BLCA) cohorts (GSE111636, GSE176307, and IMvigor210), We examined the correlation between the expression level of PLK and immunotherapy effectiveness. Next, Gene set enrichment analysis (GSEA) was evaluated to find that potentially enriched PLK signaling pathways. Utilizing TIMER 2.0, we conducted an immune infiltration analysis underlying transcriptome expression, copy number variations (CNV), or somatic mutations of PLKs in BLCA. Finally, mRNA expression validation of PLK1/3/4 by real-time PCR within 10 paired BLCA tissues, protein expression verification through the Human Protein Atlas (HPA), and PLK4 in vitro cytological studies have been employed in BLCA., Results: The expression of most of the PLK family members exhibits variation between cancerous tissues and adjacent normal tissues across various cancer species. Furthermore, the expression of PLKs demonstrates a significant association with immunotyping, infiltration of immune cell, tumor mutational burden (TMB), microsatellite instability (MSI), immunological checkpoint gene activity and therapeutic effectiveness in pan-tumor tissues. Additional investigation into the correlation between the PLK family and BLCA has revealed that the expression of the PLK genes holds substantial significance in the biological processes of BLCA. Furthermore, a notable association has been observed between the copy number variation, variant status, and the degree of certain immunological cell infiltration. Of note, the expression validation and in vitro phenotypic experiments have demonstrated that PLK4 has a significant function in promoting the BLCA cell proliferation, migration, and invasion., Conclusion: Collectively, based on various databases, our results highlight the involvement of PLK gene family in the formation of different types of tumors and identify PLK-related genes that may be used for therapy., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Aim: To evaluate correlations of tumor PLK3 with clinical features and prognosis of resectable endometrial cancer (EC) patients. Methods: Tumor tissues from 200 EC patients receiving surgical resections and adjacent tissues from 50 of them were collected for PLK3 determination using immunohistochemistry. Results: Tumor PLK3 negatively linked with myometrial invasion ≥50%, lymphovascular invasion, stromal cervical invasion, and International Federation of Gynecology and Obstetrics stage (all p < 0.050). High tumor PLK3 independently related to longer disease-free survival (DFS) (p = 0.044) and overall survival (OS) (p = 0.049). Its prognostic value was also validated by time-dependent receiver operating characteristic analyses (area under curve at most timepoints was >0.700). Conclusion: Tumor PLK3 potentially reflects prolonged DFS and OS in EC patients undergoing surgical resections.

Assay systems for evaluating compound protein-binding affinities are essential for developing agonists and/or antagonists. Targeting individual members of a protein family can be extremely important and for this reason it is critical to have methods for evaluating selectivity. We have previously reported a fluorescence recovery assay that employs a fluorescein-labelled probe to determine IC 50 values of ATP-competitive type 1 inhibitors of polo-like kinase 1 (Plk1). This probe is based on the potent Plk1 inhibitor BI2536 [fluorescein isothiocyanate (FITC)-polyethylene glycol (PEG)-lysine (Lys) (BI2536) 1]. Herein, we extend this approach to the highly homologous Plk2 and Plk3 members of this kinase family. Our results suggest that this assay system is suitable for evaluating binding affinities against Plk2 and Plk3 as well as Plk1. The new methodology represents the first example of evaluating N-terminal catalytic kinase domain (KD) affinities of Plk2 and Plk3. It represents a simple and cost-effective alternative to traditional kinase assays to explore the KD-binding compounds against Plk2 and Plk3 as well as Plk1.

Objective: This study intended to explore the relationship of PLK3 with prognosis in patients with colorectal cancer (CRC). Methods: PLK3 positivity was detected by immunohistochemistry in 160 patients with CRC receiving surgical resection. Results: The median tumor PLK3-positive rate was 26.5%. Tumor PLK3-positive rate was related to increased lymph node stage (p = 0.002) and tumor-node-metastasis stage (p < 0.001) of CRC. Tumor PLK3-positive rate ≥30% was related to shortened disease-free survival (p = 0.009) and overall survival (p = 0.003); tumor PLK3-positive rate ≥50% showed a stronger correlation with them (both p = 0.001), which was validated by multivariate Cox regression analyses (both p < 0.05). Conclusion: Tumor PLK3-positive rate ≥50% relates to increased tumor stage and unfavorable survival in patients with CRC.

The anti-proliferative activities of Novel series of 2-(4-fluorophenyl) imidazol-5-ones against MCF-7 breast cancer cell line were explored via in-slico studies which includes Quantitative structure–activity relationship QSAR, molecular docking studies, designing new compounds, and analyzing the pharmacokinetics properties of the designed compounds. From the QSAR analysis, model number one emerged the best as seen from the arithmetic assessments of (R2) = 0.6981, (R2adj) = 0.6433, (Q2) = 0.5460 and (R2pred) of 0.5357. Model number one was used in designing new derivative compounds, with higher effectiveness against estrogen positive breast cancer (MCF-7 cell line). The Molecular docking studies between the derivatives and Polo-like kinases (Plk1) receptor proved that the derivatives of 2-(4-fluorophenyl) imidazol-5-ones bind tightly to the receptor, thou ligand 24 and 27 had the highest binding affinities of −8.8 and − 9.1 kcal/mol, which was found to be higher than Doxorubicin with a docking score of −8.0 kcal/mol. These new derivatives of 2-(4-fluorophenyl) imidazol-5-ones shall be excellent inhibitors against (plk1). The pharmacokinetics analysis performed on the new structures revealed that all the structures passed the test and also the Lipinski rule of five, and they could further proceed to pre-clinical tests. They both revealed a revolution in medicine for developing novel anti-breast cancer drugs against MCF-7 cell line. [ABSTRACT FROM AUTHOR]

Background. Existing studies of PLK1 in cervical cancer had several flaws. The methods adopted by those studies of detecting PLK1 expression in cervical cancer were single and there lacks comprehensive evaluation of the clinico-pathological significance of PLK1 in cervical cancer. Methods. A total of 303 cervical tissue samples were collected for in-house tissue microarrays. Immunohistochemistry was performed for evaluating PLK1 expression between cervical cancer (including cervical squamous cell carcinoma (CESC) and cervical adenocarcinoma) and non-cancer samples. The Expression Atlas database was searched for querying PLK1 expression in different cervical cancer cell lines and different tissues in the context of pan-cancer. Standard mean difference (SMD) was calculated and the summarized receiver's operating characteristics (SROC) curves were plotted for integrated tissue microarrays, exterior high-throughput microarrays and RNA sequencing data as further verification. The effect of PLK1 expression on the overall survival, disease-free survival and event-free survival of cervical cancer patients was analyzed through Kaplan Meier survival curves for cervical cancer patients from RNA-seq and GSE44001 datasets. The gene mutation and alteration status of PLK1 in cervical cancer was inspected in COSMIC and cBioPortal databases. Functional enrichment analysis was performed for genes correlated with PLK1 from aggregated RNA-seq and microarrays. Results. A total of 963 cervical cancer samples and 178 non-cancer samples were collected from in-house tissue microarrays and exterior microarrays and RNA-seq datasets. The combined expression analysis supported overexpression of PLK1 in CESC, cervical adenocarcinoma and all types of cervical cancer (SMD D 1.59, 95%CI [0.56=2.63]; SMD D 2.99, 95%CI [0.75=5.24]; SMD D 1.57, 95% CI [0.85=2.29]) and the significant power of PLK1 expression in distinguishing CESC or all types of cervical cancer samples from non-cancer samples (AUC D 0.94, AUC D 0.92). Kaplan-Meier survival curves showed that the event-free survival rate of cervical cancer patients with higher expression of PLK1 was shorter than that of patients with lower PLK1 (HR D 2.020, P D 0:0197). Genetic alteration of PLK1 including missense mutation and mRNA low occurred in 6% of cervical cancer samples profiled in mRNA expression. Genes positively or negatively correlated with PLK1 were mainly assembled in pathways such as DNAreplication, cell cycle, mismatch repair, Ras signaling pathway, melanoma, EGFR tyrosine kinase inhibitor resistance and homologous recombination (P <0:05). Conclusions. Here, we provided sufficient evidence of PLK1 overexpression in cervical cancer. The overexpression of PLK1 in cervical cancer and the contributory effect of it on clinical progression indicated the hopeful prospect of PLK1 as a biomarker for cervical cancer. [ABSTRACT FROM AUTHOR]

Polo-like kinases (PLKs) play widely conserved roles in orchestrating meiotic chromosome dynamics. However, how PLKs are targeted to distinct subcellular localizations during meiotic progression remains poorly understood. Here, we demonstrate that the cyclin-dependent kinase CDK-1 primes the recruitment of PLK-2 to the synaptonemal complex (SC) through phosphorylation of SYP-1 in C. elegans. SYP-1 phosphorylation by CDK-1 occurs just before meiotic onset. However, PLK-2 docking to the SC is prevented by the nucleoplasmic HAL-2/3 complex until crossover designation, which constrains PLK-2 to special chromosomal regions known as pairing centers to ensure proper homologue pairing and synapsis. PLK-2 is targeted to crossover sites primed by CDK-1 and spreads along the SC by reinforcing SYP-1 phosphorylation on one side of each crossover only when threshold levels of crossovers are generated. Thus, the integration of chromosome-autonomous signaling and a nucleus-wide crossover-counting mechanism partitions holocentric chromosomes relative to the crossover site, which ultimately defines the pattern of chromosome segregation during meiosis I. [ABSTRACT FROM AUTHOR]

Background: Despite great advances in its early diagnosis and treatment, lung cancer is still an intractable disease and the second leading cause of cancer-related deaths and morbidity in the world. The family of Polo-like kinases (PLKs) consists of five serine/threonine kinases, which have been reported to participate in various human diseases. However, the expression and prognostic value of each PLK in human lung cancer have not been fully understood. This study analyzed mRNA expression and prognostic value of different PLKs in human non-small cell lung cancer (NSCLC). Methods: First, mRNA expression of PLKs in patients with NSCLC from the Oncomine and the Gene Expression Profiling Interactive Analysis (GEPIA) database was investigated. Then, a Kaplan–Meier plotter was employed for survival analysis. The sequence alteration for PLKs was analyzed using The Cancer Genome Atlas (TCGA) and the cBioPortal database. Additionally, we analyzed the association among different PLKs using the LinkedOmics database. Finally, the enrichment analysis of PLKs was achieved using the DAVID database. Results: The mRNA expression levels of PLK1 and PLK4 were significantly overexpressed, while mRNA expression level of PLK3 was underexpressed in patients with NSCLC. mRNA expressions of PLK1 and PLK4 were significantly and positively related to the tumor stage of NSCLC. Increased expressions of PLK1, PLK4, and PLK5 and decreased expression of PLK2 were attributed to limited overall survival time in NSCLC. PLK1 was positively correlated with PLK4 via the LinkedOmics database. Conclusions: PLKs are relevant targets for NSCLC treatment, especially PLK1 and PLK4. [ABSTRACT FROM AUTHOR]

No genetic association with recurrent pregnancy loss (RPL) caused by embryonic aneuploidy has been found. Recent studies have indicated that the common genetic variant rs2305957, surrounding the PLK4 gene, contributes to mitotic-origin aneuploidy risk during human early embryo development. The decrease in meiosis-specific cohesin causes predivision of sister chromatids in the centromere and chromosome segregation errors. STAG3 is a component of cohesin and is a meiosis-specific gene. Our case-control study included 184 patients with RPL whose previous products of conception (POC) exhibited aneuploidy and 190 fertile control women without a history of miscarriage. We performed a genetic association study to examine the genotype distribution at PLK4 (rs2305957) and STAG3 in patients with RPL caused by aneuploidy compared with controls. Regarding STAG3, SNPs with a minor allele frequency (MAF) threshold > 0.05 that were predicted to be binding sites of transcription factors and that showed significant associations in expression quantitative trait locus (e-QTL) analysis were selected. No significant differences in the MAF or distribution in any model of PLK4 (rs2305957) and 5 selected tag SNPs in STAG3 were found between the patients and controls. A further genome-wide association study is needed since a combination of genetic risk alleles might be useful in predicting future age-dependent RPL caused by aneuploidy. Pregnancy: Finding genes to predict recurrent pregnancy loss Researchers have ruled out two potential genetic causes of recurrent pregnancy loss (RPL). Defined as loss of two or more pregnancies at any stage, RPL is caused by loss or gain of a chromosome (aneuploidy) in almost half of cases. Identifying genetic factors could help to predict the risk of RPL, which increases with maternal age. Hiroyuki Yoshihara at Nagoya City University in Japan and co-workers investigated whether two genes involved in chromosome distribution during cell division were associated with aneuploidy-related RPL. In a study of almost 400 women, half of whom had experienced RPL, they showed that neither gene was involved. Because multiple genetic factors could combine to cause RPL, the researchers recommend a genome-wide search. A better understanding of the genetic risk factors of RPL could help women in making fertility-related choices. [ABSTRACT FROM AUTHOR]

In response to DNA damage, p53-mediated signaling is regulated by protein phosphorylation and ubiquitination to precisely control G2 checkpoint. Here we demonstrated that protein SUMOylation also engaged in regulation of p53-mediated G2 checkpoint. We found that G2 DNA damage suppressed SENP3 phosphorylation at G2/M phases in p53-dependent manner. We further found that the suppression of SENP3 phosphorylation was crucial for efficient DNA damage/p53-induced G2 checkpoint and G2 arrest. Mechanistically, we identified Cdh1, a subunit of APC/C complex, was a SUMOylated protein at G2/M phase. SENP3 could de-SUMOylate Cdh1. DNA damage/p53-induced suppression of SENP3 phosphorylation activated SENP3 de-SUMOylation of Cdh. De-SUMOylation promoted Cdh1 de-phosphorylation by phosphatase Cdc14B, and then activated APC/CCdh1 E3 ligase activity to ubiquitate and degrade Polo-like kinase 1 (Plk1) in process of G2 checkpoint. These data reveal that p53-mediated inhibition of SENP3 phosphorylation regulates the activation of Cdc14b-APC/CCdh1-Plk1 axis to control DNA damage-induced G2 checkpoint. [ABSTRACT FROM AUTHOR]

Polo-like kinases (Plks) are key cell cycle regulators. They contain a kinase domain followed by a polo-box domain that recognizes phosphorylated substrates and enhances their phosphorylation. The regulatory subunit of the Dbf4-dependent kinase complex interacts with the polo-box domain of Cdc5 (the sole Plk in Saccharomyces cerevisiae) in a phosphorylation-independent manner. We have solved the crystal structures of the polo-box domain of Cdc5 on its own and in the presence of peptides derived from Dbf4 and a canonical phosphorylated substrate. The structure bound to the Dbf4-peptide reveals an additional density on the surface opposite to the phospho-peptide binding site that allowed us to propose a model for the interaction. We found that the two peptides can bind simultaneously and non-competitively to the polo-box domain in solution. Furthermore, point mutations on the surface opposite to the phosphopeptide binding site of the polo-box domain disrupt the interaction with the Dbf4 peptide in solution and cause an early anaphase arrest phenotype distinct from the mitotic exit defect typically observed in cdc5 mutants. Collectively, our data illustrates the importance of non-canonical interactions mediated by the polo-box domain and provide key mechanistic insights into the combinatorial recognition of substrates by Polo-like kinases. [ABSTRACT FROM AUTHOR]

Diabetic cataracts can occur at an early age, causing visual impairment or blindness. The detailed molecular mechanisms of diabetic cataract formation remain incompletely understood, and there is no well-documented prophylactic agent. Galactose-fed rats and ex vivo treatment of lenses with galactose are used as models of diabetic cataract. To assess the role of histone acetyltransferases, we conducted cataract prevention screening with known histone acetyltransferase (HAT) inhibitors. Ex vivo treatment with a HAT inhibitor strongly inhibited the formation of lens turbidity in high-galactose conditions, while addition of a histone deacetylase (HDAC) inhibitor aggravated turbidity. We conducted a microarray to identify genes differentially regulated by HATs and HDACs, leading to discovery of a novel cataract causative factor, Plk3. Plk3 mRNA levels correlated with the degree of turbidity, and Plk3 inhibition alleviated galactose-induced cataract formation. These findings indicate that epigenetically controlled Plk3 influences cataract formation. Our results demonstrate a novel approach for prevention of diabetic cataract using HAT and Plk3 inhibitors. [ABSTRACT FROM AUTHOR]

Notch signaling plays a complex role in carcinogenesis, and its signaling pathway has both tumor suppressor and oncogenic components. To identify regulators that might control this dual activity of NOTCH1, we screened a chemical library targeting kinases and identified Polo-like kinase 1 (PLK1) as one of the kinases involved in arsenite-induced NOTCH1 down-modulation. As PLK1 activity drives mitotic entry but also is inhibited after DNA damage, we investigated the PLK1-NOTCH1 interplay in the G2 phase of the cell cycle and in response to DNA damage. Here, we found that PLK1 regulates NOTCH1 expression at G2/M transition. However, when cells in G2 phase are challenged with DNA damage, PLK1 is inhibited to prevent entry into mitosis. Interestingly, we found that the interaction between NOTCH1 and PLK1 is functionally important during the DNA damage response, as we found that whereas PLK1 activity is inhibited, NOTCH1 expression is maintained during DNA damage response. During genotoxic stress, cellular transformation requires that promitotic activity must override DNA damage checkpoint signaling to drive proliferation. Interestingly, we found that arsenite-induced genotoxic stress causes a PLK1-dependent signaling response that antagonizes the involvement of NOTCH1 in the DNA damage checkpoint. Taken together, our data provide evidence that Notch signaling is altered but not abolished in SCC cells. Thus, it is also important to recognize that Notch plasticity might be modulated and could represent a key determinant to switch on/off either the oncogenic or tumor suppressor function of Notch signaling in a single type of tumor. [ABSTRACT FROM AUTHOR]

Tight control of centriole duplication is critical for normal chromosome segregation and the maintenance of genomic stability. Polo-like kinase 4 (Plk4) is a key regulator of centriole biogenesis. How Plk4 dynamically promotes its symmetry-breaking relocalization and achieves its procentriole-assembly state remains unknown. Here we show that Plk4 is a unique kinase that utilizes its autophosphorylated noncatalytic cryptic polo-box (CPB) to phase separate and generate a nanoscale spherical condensate. Analyses of the crystal structure of a phospho-mimicking, condensation-proficient CPB mutant reveal that a disordered loop at the CPB PB2-tip region is critically required for Plk4 to generate condensates and induce procentriole assembly. CPB phosphorylation also promotes Plk4's dissociation from the Cep152 tether while binding to downstream STIL, thus allowing Plk4 condensate to serve as an assembling body for centriole biogenesis. This study uncovers the mechanism underlying Plk4 activation and may offer strategies for anti-Plk4 intervention against genomic instability and cancer. Regulation of centriole duplication is essential for normal chromosome segregation and the maintenance of genomic stability, and Polo-like kinase 4 (Plk4) is a known regulator with unclear mechanisms. Here the authors show that Plk4 undergoes phase separation into an assembling body through autophosphorylation which drives centriole biogenesis. [ABSTRACT FROM AUTHOR]

Polo-like kinases (PLKs) belong to a five-membered family of highly conserved serine/threonine kinases (PLK1-5) that play differentiated and essential roles as key mitotic kinases and cell cycle regulators and with this in proliferation and cellular growth. Besides, evidence is accumulating for complex and vital non-mitotic functions of PLKs. Dysregulation of PLKs is widely associated with tumorigenesis and by this, PLKs have gained increasing significance as attractive targets in cancer with diagnostic, prognostic and therapeutic potential. PLK1 has proved to have strong clinical relevance as it was found to be over-expressed in different cancer types and linked to poor patient prognosis. Targeting the diverse functions of PLKs (tumor suppressor, oncogenic) are currently at the center of numerous investigations in particular with the inhibition of PLK1 and PLK4, respectively in multiple cancer trials. Functions of PLKs and the effects of their inhibition have been extensively studied in cancer cell culture models but information is rare on how these drugs affect benign tissues and organs. As a step further towards clinical application as cancer targets, mouse models therefore play a central role. Modelling PLK function in animal models, e.g., by gene disruption or by treatment with small molecule PLK inhibitors offers promising possibilities to unveil the biological significance of PLKs in cancer maintenance and progression and give important information on PLKs’ applicability as cancer targets. In this review we aim at summarizing the approaches of modelling PLK function in mice so far with a special glimpse on the significance of PLKs in ovarian cancer and of orthotopic cancer models used in this fatal malignancy.

Glioblastoma (GBM) is the most common, aggressive, and chemorefractory primary brain tumor in adults. Identifying novel drug targets is crucial for GBM treatment. Here, we demonstrate that tubulin alpha 1a (TUBA1A) is significantly upregulated in GBM compared to low-grade gliomas (LGG) and normal tissues. High TUBA1A expression is associated with poor survival in GBM patients. TUBA1A knockdown results in mitotic arrest and reduces tumor growth in mice. TUBA1A interacts with the polo-like kinase 3 (PLK3) in the cytoplasm to inhibit its activation. This interaction licenses activation of the anaphase-promoting complex or cyclosome (APC/C) to ensure proper Foxm1-mediated metaphase-to-anaphase transition and mitotic exit. Overall, our findings demonstrate that targeting TUBA1A attenuates GBM cell growth by suppressing mitotic progression in a PLK3-dependent manner., (© 2023 Federation of European Biochemical Societies.)

Polo-like kinases (PLKs) are pivotal regulators of cell proliferation and cell survival; therefore, PLKs may be potential targets in the treatment of malignancy. The therapeutic effects of volasertib, a PLKs inhibitor for papillary and follicular thyroid cancer (known as well-differentiated thyroid cancer (WDTC)), were evaluated in this study. Volasertib inhibited cell proliferation in two papillary and two follicular thyroid cancer cell lines in a dose-dependent manner. Volasertib treatment reduced cells in the S phase and increased cells in the G2/M phase. Volasertib activated caspase-3 activity and induced apoptosis. Drug combinations of volasertib and sorafenib showed mostly synergism in four welldifferentiated thyroid carcinoma cell lines in vitro. Volasertib treatment in vivo retarded the growth of a papillary thyroid tumor model. Furthermore, the combination of volasertib with sorafenib was more effective than a single treatment of either in a follicular thyroid cancer xenograft model. Promising safety profiles appeared in animals treated with either volasertib alone or volasertib and sorafenib combination therapy. These findings support volasertib as a potential drug for the treatment of patients with WDTC. [ABSTRACT FROM AUTHOR]

The mitotic protein polo-like kinase 4 (PLK4) plays a critical role in centrosome duplication for cell division. By using immunofluorescence, we confirm that PLK4 is localized to centrosomes. In addition, we find that phospho-PLK4 (pPLK4) is cleaved and distributed to kinetochores (metaphase and anaphase), spindle midzone/cleavage furrow (anaphase and telophase), and midbody (cytokinesis) during cell division in immortalized epithelial cells as well as breast, ovarian, and colorectal cancer cells. The distribution of pPLK4 midzone/cleavage furrow and midbody positions pPLK4 to play a functional role in cytokinesis. Indeed, we found that inhibition of PLK4 kinase activity with a small-molecule inhibitor, CFI-400945, prevents translocation to the spindle midzone/cleavage furrow and prevents cellular abscission, leading to the generation of cells with polyploidy, increased numbers of duplicated centrosomes, and vulnerability to anaphase or mitotic catastrophe. The regulatory role of PLK4 in cytokinesis makes it a potential target for therapeutic intervention in appropriately selected cancers. [ABSTRACT FROM AUTHOR]

Cancer is a disease that has been the focus of scientific research and discovery and continues to remain so. Polo-like kinases (PLKs) are basically serine/threonine kinase enzymes that control cell cycle from yeast to humans. PLK-1 stands for 'Polo-like kinase-1'. It is the most investigated protein among PLKs. It is crucial for intracellular processes, hence a ' hot ' anticancer drug-target. Accelerating innovations in Enzoinformatics and associated molecular visualization tools have made it possible to literally perform a ' molecular level walk ' traversing through and observing the minutest contours of the active site of relevant enzymes. PLK-1 as a protein consists of a kinase domain at the protein N-terminal and a Polo Box Domain (PBD) at the C-terminal connected by a short inter-domain linking region. PBD has two Polo-Boxes. PBD of PLK-1 gives the impression of "a small clamp sandwiched between two clips", where the two Polo Boxes are the 'clips' and the 'phosphopeptide' is the small 'clamp'. Broadly, two major sites of PLK-1 can be potential targets: one is the adenosine-5′-triphosphate (ATP)–binding site in the kinase domain and the other is PBD (more preferred due to specificity). Targeting PLK-1 RNA and the interaction of PLK-1 with a key binding partner can also be approached. However, the list of potent small molecule inhibitors targeting the PBD site of PLK-1 is still not long enough and needs due input from the scientific community. Recently, eminent scientists have proposed targeting the 'Y'-shaped pocket of PLK-1-PBD and encouraged design of ligands that should be able to concurrently bind to two or more modules of the 'Y' pocket. Hence, it is suggested that during molecular interaction analyses, particular focus should be kept on the moiety in each ligand/drug candidate which directly interacts with the amino acid residue(s) that belong(s) to one of the three binding modules which together create this Y-shaped cavity. This obviously includes (but it is not limited to) the 'shallow cleft'-forming residues i.e. Trp414, H538 and K540, as significance of these binding residues has been consistently highlighted by many studies. The present article attempts to give a concise yet critically updated overview of targeting PLK-1 for cancer therapy. [ABSTRACT FROM AUTHOR]

Abstract α-Synuclein plays a central role in synucleinopathies pathogenesis such as Parkinson's disease (PD). Phosphorylation is the most common and important protein modification linked to α-synuclein pathologies. There is mounting evidence suggested iron and α-synuclein are closely related in PD. We previously reported iron up-regulated α-synuclein mRNA levels and induced α-synuclein aggregation. In the present study, we aimed to investigate whether and how phosphorylation was involved in iron-induced α-synuclein regulations. The results showed that iron could induce pS129 α-synuclein (phosphorylation at Ser129) and α-synuclein upregulation in the substantia nigra of iron-overloaded rats and iron-treated SH-SY5Y cells, accompanied by the elevated levels of polo-like kinase 2 (PLK2) and casein kinase 2 (CK2). Over-expression of CK2 or PLK2 induced pS129 α-synuclein up-regulation and inhibitors of CK2 or PLK2 could suppress iron-induced α-synuclein phosphorylation. Antioxidant NAC could fully block iron-induced upregulation of CK2, PLK2 and pS129 α-synuclein levels, indicating oxidative stress plays a critical role in iron-induced α-synuclein phosphorylation. However, iron-induced α-synuclein up-regulation could only be partially blocked by CK2/PLK2 inhibitor or NAC. These findings demonstrate that iron-induced oxidative stress is largely responsible for α-synuclein phosphorylation and upregulation via CK2 and PLK2, and α-synuclein upregulation is not fully phosphorylation-dependent. Highlights • Iron induced α-synuclein phosphorylation and upregulation in vivo and in vitro. • CK2 and PLK2 were involved in iron-induced α-synuclein phosphorylation. • Oxidative stress is responsible for iron-induced kinases up-regulation and α-synuclein phosphorylation. • Iron-induced α-synuclein up-regulation is not fully phosphorylation-dependent. [ABSTRACT FROM AUTHOR]

Objective: This study aims to investigate the effect of polo‐like kinase 1 (PLK1) inhibition on cisplatin (DDP)‐resistant gastric cancer (GC) cells. Methods: The transcriptional level of PLK1 was measured by quantitative reverse‐transcription polymerase chain reaction. Expressions of PLK1 and its downstream mediators as well as autophagy‐related protein LC3 I/LC3 II were detected by western blot. An 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay and 5‐ethynyl‐2′‐deoxyuridine immunofluorescent staining were conducted to evaluate the cell viability and replication activity separately. Flow cytometry was carried out to determine the cell cycle status. The GFP‐LC3 vector contributed toward tracking the formation and aggregation of autophagosomes. Results: Drug‐resistant SGC‐7901/DDP cells showed insignificant changes in all phases after DDP treatment, including DNA replication, cell proliferation, cell cycle, and apoptosis, whereas DDP could significantly improve the autophagy level of SGC‐7901/DDP as well as PLK1expression. By downregulating the expression of PLK1, both BI2536 andsi‐PLK1 enhanced SGC‐7901/DDP sensitivity to DDP, suppressing the proliferation and autophagy as well as improving the apoptosis rate. PLK1 inhibition also resulted in the repression of cell division regulators CDC25C and cyclin B1. Conclusion: Together, our experimental results illustrated that the DDP resistance of GC cells might be associated with the aberrant overexpression of PLK1. PLK1 inhibition, including si‐PLK1 and BI2536 treatment, could restore the chemosensitivity of drug‐resistant SGC‐7901/DDP cells and enhance the efficacy of DDP, revealing the potential value of PLK1 inhibition in GC chemotherapy. This study aims to investigate the effect of polo‐like kinase 1 (PLK1) inhibition on cisplatin (DDP)‐resistant gastric cancer (GC) cells. Together, our experimental results illustrated that the DDP resistance of GC cells might be associated with the aberrant overexpression of PLK1. PLK1 inhibition, including si‐PLK1 and BI2536 treatment, could restore the chemosensitivity of drug‐resistant SGC‐7901/DDP cells and enhance the efficacy of DDP, revealing the potential value of PLK1 inhibition in GC chemotherapy. [ABSTRACT FROM AUTHOR]

Background: Biological mechanism of prostate cancer (PCa) recurrence and progress is complex but many of the key elements are not fully understood. Polo-like kinases (Plks) represent a family of highly conserved serine–threonine kinases that play essential roles in cell cycle progression. Plk3 plays contradictory roles in different cancers. However, the roles of Plk3 in PCa remain largely unexplored. Methods: Kaplan–Meier analysis and Cox regression analysis were performed to evaluate the relationship between Plk3 and prognosis of patients with PCa. Gene set enrichment analysis (GSEA) was conducted to evaluate proliferation and metastasis gene sets using The Cancer Genome Atlas Dataset. MTS assay, clone formation assay, cell migration, and wound healing assay were carried out to investigate biological functions of Plk3. Results: We found that high Plk3 expression was closely correlated with poor prognosis. GSEA revealed that Plk3 was involved in proliferation and metastasis. Loss-of-function assays demonstrated that Plk3 promoted proliferation and metastasis in PCa cells in vitro. Conclusion: We discovered that Plk3 plays a critical role in PCa, indicating that it may be a potential prognostic marker and help predict the progression, especially recurrence of PCa. [ABSTRACT FROM AUTHOR]

Somatic cell nuclear transfer (SCNT) has various applications in research, as well as in the medical field and animal husbandry. However, the efficiency of SCNT is low and the accurate mechanism of SCNT in murine embryo development is unreported. In general, the developmental rate of SCNT murine embryos is lower than in vivo counterparts. In previous studies, polo-like kinase 1 (Plk1) was reported to be a crucial element in cell division including centrosome maturation, cytokinesis, and spindle formation. In an initial series of experiments in this study, BI2536, a Plk1 inhibitor, was treated to in vivo-fertilized embryos and the embryos failed to develop beyond the 2-cell stage. This confirmed previous findings that Plk1 is crucial for the first mitotic division of murine embryos. Next, we investigated Plk1's localization and intensity by immunofluorescence analysis. In contrast to normally developed embryos, SCNT murine embryos that failed to develop exhibited two types of Plk1 expressions; a low Plk1 expression pattern and ectopic expression of Plk1. The results show that Plk1 has a critical role in SCNT murine embryos. In conclusion, this study demonstrated that the SCNT murine embryos fail to develop beyond the 2-cell stage, and the embryos show abnormal Plk1 expression patterns, which may one of the main causes of developmental failure of early SCNT murine embryos. [ABSTRACT FROM AUTHOR]

Hydrophobic tagging (HT) of bioactive compounds can induce target degradation via the proteasomal pathway. The first application of hydrophobic tagging to an existing inhibitor of protein–protein interactions is now presented. We developed Poloxin‐2HT by fusing an adamantyl tag to Poloxin‐2, an inhibitor of the polo‐box domain of the protein kinase Plk1, which is a target for tumor therapy. Poloxin‐2HT selectively reduced the protein levels of Plk1 in HeLa cells and had a significantly stronger effect on cell viability and the induction of apoptosis than the untagged PBD inhibitor Poloxin‐2. The change in cellular phenotype associated with the addition of the hydrophobic tag to Poloxin‐2 demonstrated that Poloxin‐2HT targets Plk1 in living cells. Our data validate hydrophobic tagging of selective inhibitors of protein–protein interactions as a novel strategy to target and destroy disease‐relevant proteins. [ABSTRACT FROM AUTHOR]

Concordant activation of MYC and BCL-2 oncoproteins in double-hit lymphoma (DHL) results in aggressive disease that is refractory to treatment. By integrating activity-based proteomic profiling and drug screens, polo-like kinase-1 (PLK1) was identified as an essential regulator of the MYC-dependent kinome in DHL. Notably, PLK1 was expressed at high levels in DHL, correlated with MYC expression, and connoted poor outcome. Further, PLK1 signaling augmented MYC protein stability, and in turn, MYC directly induced PLK1 transcription, establishing a feed-forward MYC-PLK1 circuit in DHL. Finally, inhibition of PLK1 triggered degradation of MYC and of the antiapoptotic protein MCL-1, and PLK1 inhibitors showed synergy with BCL-2 antagonists in blocking DHL cell growth, survival, and tumorigenicity, supporting clinical targeting of PLK1 in DHL. [ABSTRACT FROM AUTHOR]

Neuroblastoma (NB) is the most common extracranial solid tumor in pediatrics, with rare occurrences of primary and metastatic tumors in the central nervous system (CNS). We previously reported the overexpression of the polo-like kinase 4 (PLK4) in embryonal brain tumors. PLK4 has also been found to be overexpressed in a variety of peripheral adult tumors and recently in peripheral NB. Here, we investigated PLK4 expression in NBs of the CNS (CNS-NB) and validated our findings by performing a multi-platform transcriptomic meta-analysis using publicly available data. We evaluated the PLK4 expression by quantitative real-time PCR (qRT-PCR) on the CNS-NB samples and compared the relative expression levels among other embryonal and non-embryonal brain tumors. The relative PLK4 expression levels of the NB samples were found to be significantly higher than the non-embryonal brain tumors (p-value < 0.0001 in both our samples and in public databases). Here, we expand upon our previous work that detected PLK4 overexpression in pediatric embryonal tumors to include CNS-NB. As we previously reported, inhibiting PLK4 in embryonal tumors led to decreased tumor cell proliferation, survival, invasion and migration in vitro and tumor growth in vivo, and therefore PLK4 may be a potential new therapeutic approach to CNS-NB. [ABSTRACT FROM AUTHOR]