title: Staurosporine induces megakaryocytic differentiation through the upregulation of JAK/Stat3 signaling pathway.
abstract: The induction of megakaryocyte (MK) differentiation is a potent strategy for the clinical treatment of diseases related to blood platelet disorders. Staurosporine (STS) is an inhibitor of protein kinase C (PKC) with an inhibitory effect on cancer cells through apoptosis induction. However, the exact mechanism of STS on MK differentiation is still unclear. The present study assessed the regulatory effect of STS on MK differentiation in both human leukemia cells and mouse bone marrow-derived stem cells. STS not only inhibited the proliferation of both K562 and HEL cell lines, but also induced the cell differentiation into MK lineage, resulting in polyploidy formation, MK-specific markers CD41 and CD61 expression, and platelet factor 4 (PF4) secretions of cells. The induction effect of STS was upregulated through the expression of Stat3, but not PKC. The level of phosphorylated (p)-Stat3 showed an increased expression, translocated to the nucleus, and enhanced the DNA-binding activity in STS-treated cells. Blockage Stat3 and its upstream molecule JAK by Stat3 inhibitor VI and JAK inhibitor I, respectively, demonstrated that the cells obviously reduced the percentage of STS-mediated MK differentiation. Further investigation of the cells with Stat3 siRNA transfection showed that p-Stat3 and MK differentiation was markedly decreased, indicating that Stat3 is an important molecule in inducing MK differentiation. Additionally, the ex vivo assay also confirmed that STS effectively stimulated CFU-MK colony formation and CD61 expression in bone marrow cells. In conclusion, STS is a potent inducer for MK differentiation through the upregulation of JAK/Stat3 signaling pathway and p-Stat3 nuclear translocation.
authors.affiliation: Department of Biochemical Science and Technology, National Chiayi University, Chiayi 600, Taiwan.
authors.forename: Hsuan-Yu
authors.initials: HY
authors.lastname: Peng
authors.forename: Hui-Fen
authors.initials: HF
authors.lastname: Liao
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D053612:Janus Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D020014:K562 Cells; D008533:Megakaryocytes / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D034741:RNA, Small Interfering / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D019311:Staurosporine / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D053612:Janus Kinases; D019311:Staurosporine