thiostrepton and Pancreatic-Neoplasms

Ferroptosis is a new form of regulated cell death that is mediated by intracellular iron and ester oxygenase, and glutathione-dependent lipid hydroperoxidase glutathione peroxidase 4 (GPX4) prevents ferroptosis by converting lipid hydroperoxides into nontoxic lipid alcohols. Although thiostrepton (TST) has been reported to exert antitumor effects, its role in pancreatic cancer and the underlying mechanisms remain unclear. In this study, we found that TST reduced the viability and clonogenesis of pancreatic cancer cell lines, along with intracellular iron overload, increasing reactive oxygen species (ROS) accumulation, malondialdehyde (MDA) overexpression, and glutathione peroxidase (GSH-PX) depletion. Mechanistically, chromatin immunoprecipitation (ChIP) and dual luciferase reporter gene assays were used to confirm that signal transducer and activator of transcription 3 (STAT3) binds to the GPX4 promoter region and promotes its transcription, whereas TST blocked GPX4 expression by regulating STAT3. Finally, in vivo experiments revealed that TST inhibited the growth of subcutaneously transplanted tumours and had considerable biosafety. In conclusion, our study identified the mechanism by which TST-induced ferroptosis in pancreatic cancer cells through STAT3/GPX4 signalling.

Topics: Ferroptosis; Humans; Lipid Peroxides; Pancreatic Neoplasms; Phospholipid Hydroperoxide Glutathione Peroxidase; STAT3 Transcription Factor; Thiostrepton

Forkhead box transcription factor M1 (FOXM1) is a proliferation-associated transcription factor involved in tumorigenesis through transcriptional regulation of its target genes in various cells, including dendritic cells (DCs). Although previous work has shown that FOXM1 enhances DC maturation in response to house dust mite allergens, it is not known whether FOXM1 affects DC maturation in the context of tumor-specific immunity. In this study, we examined the central role of FOXM1 in regulating bone marrow-derived dendritic cell (BMDC) maturation phenotypes and function in pancreatic cancer and colon cancer. FOXM1 retarded maturation phenotypes of BMDCs, inhibited promotion of T-cell proliferation, and decreased interleukin-12 (IL-12) p70 in tumor-bearing mice (TBM). Notably, FOXM1 expression was epigenetically regulated by dimethylation on H3 lysine 79 (H3K79me2), a modification present in both tumor cells and BMDCs. Increased H3K79me2 enrichment was observed at the FOXM1 promoter in both BMDCs from TBM, and in BMDCs from wild-type mice cultured with tumor-conditioned medium that mimics the tumor microenvironment (TME). Furthermore, inhibition of the H3K79 methyltransferase DOT1L not only decreased enrichment of H3K79me2, but also downregulated expression of FOXM1 and partially reversed its immunosuppressive effects on BMDCs. Furthermore, we found that FOXM1 upregulated transcription of Wnt family number 5A (Wnt5a) in BMDCs in vitro; we also observed that exogenous Wnt5a expression abrogated BMDC maturation phenotypes by inhibiting FOXM1 and H3K79me2 modification. Therefore, our results reveal that upregulation of FOXM1 by H3K79me2 in pancreatic cancer and colon cancer significantly inhibits maturation phenotypes and function of BMDCs through the Wnt5a signaling pathway, and thus provide novel insights into FOXM1-based antitumor immunotherapy.

Topics: Adenocarcinoma; Adenosine; Animals; Bone Marrow Cells; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Culture Media, Conditioned; Dendritic Cells; Epigenesis, Genetic; Forkhead Box Protein M1; Gene Expression Regulation, Neoplastic; Histone-Lysine N-Methyltransferase; Histones; Humans; Lysine; Male; Methylation; Mice, Inbred BALB C; Mice, Inbred C57BL; Models, Biological; Pancreatic Neoplasms; Phenylurea Compounds; Signal Transduction; Thiostrepton; Wnt-5a Protein