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Ferroptosis is recently discovered programmed cell death, induced by cellular ferrous ion bursts and subsequent Fenton reactions. The iron source in tumor cells is limited due to tightly controlled iron metabolism. Since hierarchical iron architecture is rarely considered in ferroptosis cancer treatment, multilayer Fe2O3 architectures (UF@PPDF NPs) are developed by modulating ultra‐small γ‐Fe2O3 nanocrystal assemblies, and further conjugating cancer cell targeting folic acid (FA), chemotherapeutic drug doxorubicin (Dox). Hierarchically assembled γ‐Fe2O3 nanocrystal facilitates switchable magnetic resonance imaging (MRI), much enhanced ferroptosis efficiency, and very high second near‐infrared (NIR‐II) photothermal conversion. For MRI, UF@PPDF nanoparticles (NPs) enables clearly visualized tissues in terms of size and compactness, with dynamic T2‐T1 imaging switching. UF@PPDF NPs exhibits highly efficient photothermal therapy (PTT) upon NIR‐II irradiation, together with controlled release of ferric ions and Dox, thus achieving PTT‐chemotherapy‐ferroptosis trifunctional synergistic cancer therapy for tumor ablation. RNA sequencing analyses of differentially expressed genes implies a multifaceted role for this therapy in cancer cell signaling. Cellular respiration and electron transport are significantly upregulated, while the epigenetic pathways, including chromatin modification and RNA transcription activity are severely downregulated, with an overall effect of cellular apoptosis. Thus, γ‐Fe2O3 architectures provide new possibility for highly efficient deep tumor treatment. [ABSTRACT FROM AUTHOR]

Esophageal squamous cell carcinomas (ESCCs) have a poor prognosis mostly due to early metastasis. To explore the early event of metastasis in ESCC, we established an in vitro selection model to mimic the interaction of tumor cells with extracellular matrix, through which a sub-line of ESCC cells with high invasive ability was generated. By comparing the gene expression profile of the highly invasive sub-line to that of the parental cells, ADAM12-L was identified as a candidate gene promoting ESCC cell invasion. Immunohistochemistry revealed that the ADAM12-L was overexpressed in human ESCC tissues, especially at cancer invasive edge, and ADAM12-L overexpression tightly correlated with increased metastasis and poor outcome of ESCC patients. Indeed, ADAM12-L knockdown reduced the invasion and metastasis of ESCC cells both in vitro and in vivo. Furthermore, we demonstrated that ADAM12-L participated in focal adhesion turnover and promoted the activation of focal adhesion kinase (FAK), which in turn increased ADAM12-L transcription through FAK/JNK/c-Jun axis. Therefore, a loop initiated from the cancer cell upon the engagement with extracellular matrix through FAK and c-Jun to enhance ADAM12-L expression is established, leading to the positive feedback of further FAK activation and prompting metastasis. Our study indicates that overexpression of ADAM12-L can serve as a precision marker to determine the activation of this loop. Targeting ADAM12-L to disrupt this positive feedback loop represents a promising strategy to treat the metastasis of esophageal cancers. [ABSTRACT FROM AUTHOR]

Cancer stem cells (CSCs) are the subpopulation of tumor cells with the properties of tumorigenesis, multilineage differentiation potential and self-renewal, which is the driving force of tumor recurrence and metastasis. However, targeting CSCs is still the main challenge in cancer therapy due to their rapid growth and fast mutation rate. Herein, we developed a simple strategy of photodynamic therapy (PDT) targeting CSCs, dependent on much more abundant ribosomes in CSCs. The interactions between positively charged nanoparticles with negatively charged nucleic acids architectures in cancer cells could lead ribosomes targeting as well as CSCs targeting. The co-assembly of simple amino porphyrin (m -TAPP) with short peptide (Fmoc-L 3 -OMe) formed nanoparticles (NPs) with good biocompatibility and photoactivity, became positively charged due to low pH value of tumour microenvironment, and efficiently accessed cancer cell ribosome, approached cancer cell nuclei, therefore enriched in the fast-amplifying CSCs. The inhibitive effect on CSCs by m -TAPP assemblies was verified by the significant reduction of CSCs markers CD44, CD133 and ribosome amount in cancer cells and tissues. Upon light irradiation, the NPs induced ROS generation to provoke destructive cancer cell ribosome damage and subsequent apoptosis to prevent tumor growth markedly. Based on the assemblies of small organic molecules, our study not only achieves ribosome degradation induced cancer cells apoptosis, but also indicates new possibility of performing CSCs targeting PDT. [ABSTRACT FROM AUTHOR]

Abstract: Deoxypodophyllotoxin (DPT), a naturally occurring microtubule destabilizer, inhibits tubulin polymerization and causes cell cycle arrest at G2/M phase in tumor cells. However, the anti-tumor effect and specific mechanism of DPT in non-small cell lung cancer (NSCLC) are still poorly understood. In this study, we determined the anti-tumor effect and potential mechanism of DPT in the NSCLC cell line, NCI-H460 (H460). First, we demonstrated that DPT significantly inhibits the proliferation of H460 cells in vitro and the growth of H460 xenografts in vivo. In further studies, DPT triggered necroptosis in H460 cells with the following characteristics: (I) necrotic cell death morphology; (II) autophagy; (III) loss of plasma membrane integrity; (IV) loss of mitochondria membrane potential; (V) elevation of reactive oxygen species levels; and (VI) specific inhibition of necroptosis via a small molecule, necrostatin-1. This study also revealed that DPT has a similar effect towards the drug-sensitive cancer cell line, H460, and the drug-resistant cell line, H460/Bcl-xL. To our knowledge, this is the first report to document the induction of necroptosis by a microtubule-targeting agent to circumvent cancer drug resistance, thereby providing a new potential choice for clinical cancer therapy, especially drug-resistant cancer therapy. [Copyright &y& Elsevier]

Abstract: Non-metastatic cells 5 (NME5), a recently found gene belonging to the NDPK-like molecules gene family, is highly expressed in testis and some types of human cancer. Current studies have revealed diverse potential functions of NME5 and we have reported that NME5 is associated with innate resistance to gemcitabine in human pancreatic cancer cells in previous study. However, the mechanism underlying the transcriptional regulation of NME5 has not been elucidated yet. In this study, we analyzed the 5′-flanking region of the human NME5 gene and revealed its transcription start site (TSS) at −35bp relative to its translation start codon ATG. Using 5′ unidirectional deletion analysis, we demonstrated that the proximal promoter of NME5 is located within −1051bp to +35bp. Two functional GC-boxes (−300bp and −323bp) were identified within the promoter region. Mutation of either GC-box led to significant reduction in NME5 promoter activity, whereas overexpression of Sp1 activated NME5 promoter activity in MIA PaCa-2 and 293T cells. In silico analysis predicted that transcription factor Sp1 binds to both GC-boxes, which were confirmed by EMSA and ChIP. In addition, we found that compared with MIA PaCa-2, Sp1 was highly expressed in PAXC002, a well characterized human pancreatic cancer cell line with innate gemcitabine resistance where NME5 was reported to be highly expressed, indicating that Sp1 induces NEM5 expression in PAXC002 cells. In conclusion, our study characterized for the first time the human NME5 promoter which is controlled by Sp1 transcription factor in pancreatic cancer. [Copyright &y& Elsevier]

Gastric cancer stem cells (GCSCs) have been used as a therapeutic target. This study aims to estimate the role of miR-98-5p (termed miR-98) in the development of GCSCs. The expression of miR-98 in CD44+ GCSCs was verified by RT-PCR. The miR-98 was overexpressed in CD44+ GCSCs by Lentivirus. The ability of self-renewal, invasion, chemoresistance and tumorigenicity was detected in vitro or in vivo after overexpression of miR-98. The target genes of miR-98 were predicted and verified by luciferase reporter assays. The effects miR-98 / BCAT1 signaling on the chemoresistance and tumorigenicity of CD44+ GCSCs were investigated in a xenograft model by rescue experiments. We have shown that miR-98 was decreased in CD44+ GCSCs. The overexpression of miR-98 could inhibit the expression of stem-related genes and the ability of self-renewal, invasion, and tumorigenicity of GCSCs. Also, we found that miR-98 overexpression enhances the sensitivity to cisplatin treatment in vitro. Using a xenograft model, we showed that miR-98 overexpression reversed paclitaxel resistance to CD44+ GCSCs. Finally, we found that branched-chain aminotransferases 1 (BCAT1) is a target gene of miR-98. Overexpressed BCAT1 reversed xenograft tumor formation ability and attenuated the paclitaxel chemosensitivity induced by miR-98 downregulation. Furthermore, BCAT1 restoration affected the expression of invasion and drug resistance-related genes. This study revealed miR-98 inhibits gastric cancer cell stemness and chemoresistance by targeting BCAT1, suggesting that this miR-98 / BCAT1 axis represents a potential therapeutic target in gastric cancer. [ABSTRACT FROM AUTHOR]