title: 4SC-202 activates ASK1-dependent mitochondrial apoptosis pathway to inhibit hepatocellular carcinoma cells.
abstract: The aim of the present study is to investigate the potential anti-hepatocellular carcinoma (HCC) cell activity by 4SC-202, a novel class I HDAC inhibitor (HDACi). The associated signaling mechanisms were also analyzed. We showed that 4SC-202 treatment induced potent cytotoxic and proliferation-inhibitory activities against established HCC cell lines (HepG2, HepB3, SMMC-7721) and patient-derived primary HCC cells. Further, adding 4SC-202 in HCC cells activated mitochondrial apoptosis pathway, which was evidenced by mitochondrial permeability transition pore (mPTP) opening, cytochrome C cytosol release and caspase-3/-9 activation. Inhibition of this apoptosis pathway, by caspase-3/-9 inhibitors, mPTP blockers, or by shRNA-mediated knockdown of cyclophilin-D (Cyp-D, a key component of mPTP), significantly attenuated 4SC-202-induced HCC cell death and apoptosis. Reversely, over-expression of Cyp-D enhanced 4SC-202's sensitivity in HCC cells. Further studies showed that 4SC-202 induced apoptosis signal-regulating kinase 1 (ASK1) activation, causing it translocation to mitochondria and physical association with Cyp-D. This mitochondrial ASK1-Cyp-D complexation appeared required for mediating 4SC-202-induced apoptosis activation. ASK1 stable knockdown by targeted-shRNAs largely inhibited 4SC-202-induced mPTP opening, cytochrome C release, and following HCC cell apoptotic death. Together, we suggest that 4SC-202 activates ASK1-dependent mitochondrial apoptosis pathway to potently inhibit human HCC cells.
authors.affiliation: Department of Infectious Disease, Linyi People's Hospital, Linyi 276000, China. Electronic address: fumeilidrlinyi@tom.com.
authors.forename: Meili
authors.initials: M
authors.lastname: Fu
authors.affiliation: Department of Head and Neck Surgery, Linyi Tumor Hospital, Linyi 276000, China.
authors.forename: Fuqiang
authors.initials: F
authors.lastname: Wan
authors.affiliation: Department of Nursing, Tengzhou Central People's Hospital, Tengzhou 277500, China.
authors.forename: Zhengling
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Operating Room, Linyi People's Hospital, Linyi 276000, China.
authors.forename: Fenghua
authors.initials: F
authors.lastname: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage*; D006801:Humans; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism*; D008928:Mitochondria / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human
keywords: 4SC-202; ASK1 and cyclophilin-D; HDAC inhibitor; Hepatocellular carcinoma (HCC); Mitochondrial apoptosis pathway