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Background: Bladder cancer (BC) is one of the most common malignancies of the genitourinary system. Phosphofructokinase 1 (PFK-1) is one of member of PFK, which plays an important role in reprogramming cancer metabolism, such as lactylation modification. Zinc finger E-box-binding homeobox 1 (ZEB1) has been demonstrated to be a oncogene in many cancers. Therefore, this study was performed to explore the effects of PFK-1 on the lactylation of ZEB1 in BC development. Methods: Cell viability was measured using the CCK-8 kit. The glucose assay kit and lactate assay kit were used to detect glucose utilization and lactate production. The DNA was purified and quantified by qRT-PCR. Results: In the present study, we found that ZEB1 expression levels were significantly elevated in bladder cancer cells. Impaired PFK-1 expression inhibits proliferation, migration, and invasion of BC cells and suppresses tumour growth in vivo. We subsequently found that knockdown of PFK-1 decreases glycolysis, including reduced glucose consumption, lactate production and total extracellular acidification rate (ECAR). Mechanistically, PFK-1 inhibits histone lactylation of bladder cancer cells, and thus inhibits the transcription activity of ZEB1. Conclusion: Our results suggest that PFK-1 can inhibit the malignant phenotype of bladder cancer cells by mediating the lactylation of ZEB1. These findings suggested PFK-1 to be a new potential target for bladder cancer therapy. [ABSTRACT FROM AUTHOR]

Except for cell-surface receptors, a range of transporters have been exploited as targets for the delivery of novel anti-tumour nanomaterials. Transporters, which are essential for delivering nutrients for the biosynthesis of mammalian cells, are significantly expressed in a range of tumour types; their expression is mostly tissue- and site-specific. The unique functional and expression characteristics of transporters make them ideal targets for mediating the selective delivery of nanomaterials to cancer cells, thus promoting cell accumulation, and enhancing the penetration of nanomaterials into biological barriers before they can specifically target cancer cells. In this review, we discuss the unique function of cancer-related transporters in the initiation and development of tumours, as well as the use of transporter-targeted nanocarriers in tumour-targeting therapy. First, the expression of various transporters in tumorigenesis and development is reviewed; this is followed by a discussion of the latest advances in targeted drug delivery strategies based on transporter nanocarriers. Finally, we review the molecular mechanisms and targeting efficiency of transporter-mediated nanocarriers. This review provides a state-of-the-art synthesis of this discipline and will facilitate the generation of new concepts for the design of highly efficacious and tumour-targeting nanocarriers. [ABSTRACT FROM AUTHOR]

DNA topoisomerases are essential nuclear enzymes in correcting topological DNA errors and maintaining DNA integrity. Topoisomerase inhibitors are a significant class of cancer chemotherapeutics with a definite curative effect. Natural products are a rich source of lead compounds for drug discovery, including anti-tumor drugs. In this study, we found that narciclasine (NCS), an amaryllidaceae alkaloid, is a novel inhibitor of topoisomerase I (topo I). Our data demonstrated that NCS inhibited topo I activity and reversed its unwinding effect on p-HOT DNA substrate. However, it had no obvious effect on topo II activity. The molecular mechanism of NCS inhibited topo I showed that NCS did not stabilize topo-DNA covalent complexes in cells, indicating that NCS is not a topo I poison. A blind docking result showed that NCS could bind to topo I, suggesting that NCS might be a topo I suppressor. Additionally, NCS exhibited a potent anti-proliferation effect in various cancer cells. NCS arrested the cell cycle at G2/M phase and induced cell apoptosis. Our study reveals the antitumor mechanisms of NCS and provides a good foundation for the development of anti-cancer drugs based on topo I inhibition. [ABSTRACT FROM AUTHOR]

Over the past decade, immunotherapy has emerged as one of the most promising approaches to cancer treatment. The use of immune checkpoint inhibitors has resulted in impressive and durable clinical responses in the treatment of various cancers. Additionally, immunotherapy utilizing chimeric antigen receptor (CAR)-engineered T cells has produced robust responses in blood cancers, and T cell receptor (TCR)-engineered T cells are showing promising results in the treatment of solid cancers. Despite these noteworthy advancements in cancer immunotherapy, numerous challenges remain. Some patient populations are unresponsive to immune checkpoint inhibitor therapy, and CAR T cell therapy has yet to show efficacy against solid cancers. In this review, we first discuss the significant role that T cells play in the body's defense against cancer. We then delve into the mechanisms behind the current challenges facing immunotherapy, starting with T cell exhaustion due to immune checkpoint upregulation and changes in the transcriptional and epigenetic landscapes of dysfunctional T cells. We then discuss cancer-cell-intrinsic characteristics, including molecular alterations in cancer cells and the immunosuppressive nature of the tumor microenvironment (TME), which collectively facilitate tumor cell proliferation, survival, metastasis, and immune evasion. Finally, we examine recent advancements in cancer immunotherapy, with a specific emphasis on T-cell-based treatments. [ABSTRACT FROM AUTHOR]

Purpose. Lung cancer is a relatively common type of cancer, and the incidence rate has been on the rise in recent years. MicroRNAs are a class of endogenous small RNA molecules, which are essential for the posttranscriptional regulation of genes. miR-29b is closely related to the occurrence and development of tumors, including prostate cancer, colon cancer, and breast cancer. However, few studies have been performed to explore the expression and pathway of miR-29b in non-small-cell lung cancer (NSCLC). Methods. Using bioinformatics analysis, we found that patients with low relative expression of the miR-29b gene have a low long-term survival rate. The results of in vitro research showed that when miR-29b expression was upregulated, the invasion, migration, and proliferation of A549 and NCI-H-1792 cells was inhibited, and the apoptosis was accelerated. Results. The results showed that FEM1B is a miR-29b target gene, and the expressions of FEM1B and miR-29b were negatively correlated. Like the upregulation of miR-29b expression, silencing the FEM1B expression could also impair the invasion, migration, and proliferation abilities of A549 and NCI-H-1792 cells. When FEM1B expression was restored, the inhibitory effect of miR-29b could be reversed. Reverse transcription-polymerase chain reaction (RT-PCR) and western blot (WB) analysis showed that overexpression of miR-29b could inhibit the expression of FEM1B, AKT, vascular endothelial growth factor (VEGF), and Sirt3 in A549 and NCI-H-1792 cells and upregulate the expression of FOXO1 protein. Conclusion. The results of this study indicate that miR-29b inhibits the proliferation and deterioration of NSCLC cells by targeting FEM1B and inhibiting the activation of the FOXO1/AKT pathway. miR-29b may become a new target for the clinical diagnosis and treatment of lung cancer, and it is expected to become a new inhibitor of NSCLC. [ABSTRACT FROM AUTHOR]

Background: In tumor treatment, protein tyrosine kinase inhibitors (TKIs) have been extensively utilized. However, the efficacy of TKI is significantly compromised by drug resistance. Consequently, finding an effective solution to overcome TKI resistance becomes crucial. Reactive oxygen species (ROS) are a group of highly active molecules that play important roles in targeted cancer therapy including TKI targeted therapy. In this review, we concentrate on the ROS-associated mechanisms of TKI lethality in tumors and strategies for regulating ROS to reverse TKI resistance in cancer. Main body: Elevated ROS levels often manifest during TKI therapy in cancers, potentially causing organelle damage and cell death, which are critical to the success of TKIs in eradicating cancer cells. However, it is noteworthy that cancer cells might initiate resistance pathways to shield themselves from ROS-induced damage, leading to TKI resistance. Addressing this challenge involves blocking these resistance pathways, for instance, the NRF2-KEAP1 axis and protective autophagy, to promote ROS accumulation in cells, thereby resensitizing drug-resistant cancer cells to TKIs. Additional effective approaches inducing ROS generation within drug-resistant cells and providing exogenous ROS stimulation. Conclusion: ROS play pivotal roles in the eradication of tumor cells by TKI. Harnessing the accumulation of ROS to overcome TKI resistance is an effective and widely applicable approach. [ABSTRACT FROM AUTHOR]

CircRNAs represent a new class of non‐coding RNAs which show aberrant expression in diverse cancers, such as gastric cancer (GC). circSTRBP, for instance, is suggested to be overexpressed in GC cells and tissues. However, the biological role of circSTRBP in the progression of GC and the potential mechanisms have not been investigated. circSTRBP levels within GC cells and tissues were measured by RT‐qPCR. The stability of circSTRBP was assessed by actinomycin D and Ribonuclease R treatment. Cell proliferation, migration, invasion and in vitro angiogenic abilities after circSTRBP knockdown were analysed through CCK‐8 assay, transwell culture system and the tube formation assay. The interaction of circSTRBP with the predicted target microRNA (miRNA) was examined by RNA immunoprecipitation and luciferase reporter assays. Xenograft tumour model was established to evaluate the role of exosomal circSTRBP in the tumour formation of GC cells. circSTRBP was upregulated in GC cells and tissues, and there was an increased level of circSTRBP in GC‐derived exosomes. circSTRBP in the exosomes enhanced GC cell growth and migration in vitro, which modulates E2F Transcription Factor 2 (E2F2) expression through targeting miR‐1294 and miR‐593‐3p. Additionally, exosomal circSTRBP promoted the tumour growth of GC cells in the xenograft model. Exosomal circSTRBP is implicated in the progression of GC by modulating the activity of miR‐1294/miR‐593‐3p/E2F2 axis. [ABSTRACT FROM AUTHOR]

Increasing evidence indicate that cancer stem cells (CSCs) are the key driver of tumor initiation and recurrence. The cellular and soluble components of the tumor microenvironment (TME) impact on cancer initiation and progression, such as cytokines and chemokines. Thus, targeting CSCs and TME is a novel anti-cancer approach. Resveratrol (RES), a bioactive phytochemical extracted from various plants, exhibits tumor-suppressing activities in lung cancer, yet the mechanism remains poorly understood. Our data showed that the expression level of IL-6 was positively correlated with the presence of lung cancer stem-like cells (LCSCs) in human lung cancer tissues. In vitro results showed that IL-6 was highly elevated in lung cancer sphere-forming cells and could enhance the stemness of LCSCs, including tumor sphere formation ability, the percentage of CD133 positive cells, and the expression of LCSC specific markers (CD133, ALDH1A1 and Nanog). Simultaneously, our results confirmed that RES effectively inhibited LCSC properties, downregulated Wnt/β-catenin signaling and reduced IL-6 level in vitro and in vivo. Furthermore, we found RES treatment attenuated the activation of Wnt/β-catenin signaling by LiCl (GSK3β agonist). IL-6-promoted LCSC properties and Wnt/β-catenin signaling was also reversed by RES. Taken together, these data illustrated that RES inhibited lung cancer by targeting LCSCs and IL-6 in TME. The novel findings from this study provided evidence that RES exhibited multi-target effects on suppression of lung cancer and could be a novel potent cancer-preventive compound. [ABSTRACT FROM AUTHOR]

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Trophoblast cell surface antigen 2 (Trop2) has emerged as a potential target for effective cancer therapy. In this study, we report a novel anti-Trop2 antibody IMB1636, developed using hybridoma technology. It exhibited high affinity and specificity (K D = 0.483 nM) in binding both antigens and cancer cells, as well as human tumor tissues. hIMB1636 could induce endocytosis, and enabled targeted delivery to the tumor site with an in vivo retention time of 264 h. The humanized antibody hIMB1636, acquired using CDR grafting, exhibited the potential to directly inhibit cancer cell proliferation and migration, and to induce ADCC effects. Moreover, hIMB1636 significantly inhibited the growth of MDA-MB-468 xenograft tumors in vivo. Mechanistically, hIMB1636 induced cell cycle arrest and apoptosis by regulating cyclin-related proteins and the caspase cascade. In comparison to commercialized sacituzumab, hIMB1636 recognized a conformational epitope instead of a linear one, bound to antigen and cancer cells with similar binding affinity, induced significantly more potent ADCC effects against cancer cells, and displayed superior antitumor activities both in vitro and in vivo. The data presented in this study highlights the potential of hIMB1636 as a carrier for the formulation of antibody-based conjugates, or as a promising candidate for anticancer therapy. • A novel anti-Trop2 humanized antibody hIMB1636 with high affinity and specificity was produced. • hIMB1636 can induce endocytosis, and enables targeted delivery to the tumor site in vivo. • hIMB1636 shows similar affinity, stronger ADCC and antitumor effects in contrast with sacituzumab. • hIMB1636 can serve as a carrier for conjugates, or potentially be utilized as a promising drugs. [ABSTRACT FROM AUTHOR]