title: GYY4137, a hydrogen sulfide (H₂S) donor, shows potent anti-hepatocellular carcinoma activity through blocking the STAT3 pathway.
abstract: GYY4137, a hydrogen sulfide (H2S) donor, exhibits anticancer activity by a combination of cell cycle arrest and promoting apoptosis, and inhibits tumor growth, however, the precise mechanisms involved remain unclear. In this study, we discovered that GYY4137-mediated suppression of cell proliferation in human hepatocellular carcinoma (HCC) cell lines and tumor growth in a subcutaneous HepG2 xenograft model may be due to directly targeting the signal transducer and activator of transcription 3 (STAT3) pathway. We found that GYY4137 suppressed STAT3 activation by reducing p-STAT3 (Y705) levels effectively in HepG2 and Bel7402 cells. Altered expression levels of STAT3-regulated downstream proteins including Bcl-2, cyclin D1, Mcl-1, survivin, vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α (HIF-1α) may contribute to the inhibition of G1/S cell cycle transition and angiogenesis. Increased cleaved caspase-9, caspase-3 and poly(ADP-ribose) polymerase (PARP) cleavage may induce cell apoptosis in HepG2 and Bel7402 cells. In vivo, GYY4137 significantly inhibited tumor growth in the subcutaneous HepG2 xenograft model by inhibiting STAT3 activation and its target gene expression. These results suggest that GYY4137-mediated suppression of HCC growth may be due to the inhibition of the STAT3 pathway.
authors.affiliation: Center of Liver Transplantation, The First Affiliated Hospital of Nanjing Medical University, The Key Laboratory of Living Donor Liver Transplantation, Ministry of Health, Nanjing 210029, P.R. China.
authors.forename: Sen
authors.initials: S
authors.lastname: Lu
authors.affiliation: Center of Liver Transplantation, The First Affiliated Hospital of Nanjing Medical University, The Key Laboratory of Living Donor Liver Transplantation, Ministry of Health, Nanjing 210029, P.R. China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Center of Liver Transplantation, The First Affiliated Hospital of Nanjing Medical University, The Key Laboratory of Living Donor Liver Transplantation, Ministry of Health, Nanjing 210029, P.R. China.
authors.forename: Xinli
authors.initials: X
authors.lastname: Huang
authors.affiliation: Center of Liver Transplantation, The First Affiliated Hospital of Nanjing Medical University, The Key Laboratory of Living Donor Liver Transplantation, Ministry of Health, Nanjing 210029, P.R. China.
authors.forename: Xuehao
authors.initials: X
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D056945:Hep G2 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis; D015850:Interleukin-6 / Q000378:metabolism; D053614:Janus Kinase 2 / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009025:Morpholines / Q000494:pharmacology*; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D009946:Organothiophosphorus Compounds / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D023041:Xenograft Model Antitumor Assays
chemical_list: C529376:GYY 4137; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C508600:IL6 protein, human; D015850:Interleukin-6; D009025:Morpholines; D009946:Organothiophosphorus Compounds; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D011065:Poly(ADP-ribose) Polymerases; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D053148:Caspase 3; D053453:Caspase 9