title: GADD45β induction by S-adenosylmethionine inhibits hepatocellular carcinoma cell proliferation during acute ischemia-hypoxia.
abstract: Growth arrest DNA damage-inducible gene 45β (GADD45β), which influences cell growth, apoptosis and cellular response to DNA damage, is downregulated in hepatocellular carcinoma (HCC). S-adenosylmethionine (SAMe) serves as an essential methyl donor in multiple metabolic pathways and is a polyamine and glutathione (GSH) precursor. In this study, we assessed the roles of GADD45β and SAMe in cell survival during acute ischemia-hypoxia (I/H). SAMe treatment induced growth of HL-7702 normal hepatic cells, but decreased the viability of HepG2 (p53 wild-type) and Hep3B (p53 null) HCC cells. Cells were exposed to I/H with or without SAMe pre-treatment. I/H exposure alone triggered HCC cell proliferation promoted by autophagy. SAMe pre-treatment restored GADD45β expression and activated HCC cell apoptosis and eliminated I/H-induced HCC cell proliferation. p53 loss blunted the response to SAMe and I/H exposure in Hep3B cells; thus, the inhibitory effect of SAMe on cell proliferation may be reduced in p53-null cells as compared to wild-type cells. These results indicate that GADD45β induction by SAMe inhibits HCC cell proliferation during I/H as a result of increased apoptosis, and that SAMe also protects normal hepatocytes from apoptotic cell death and promotes normal cell regeneration. SAMe should be considered a potential therapeutic agent for the management of HCC.
authors.affiliation: Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Ding
authors.initials: D
authors.lastname: Ma
authors.affiliation: Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Baiyong
authors.initials: B
authors.lastname: Shen
authors.affiliation: Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Varun
authors.initials: V
authors.lastname: Seewoo
authors.affiliation: Department of Surgery, Huadong Hospital, Shanghai, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Tong
authors.affiliation: Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Weiping
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Jin
authors.affiliation: Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Chenghong
authors.initials: C
authors.lastname: Peng
authors.affiliation: Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Weihua
authors.initials: W
authors.lastname: Qiu
mesh_terms: D000943:Antigens, Differentiation / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy; D000071193:Autophagy-Related Protein 7 / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects*; D015536:Down-Regulation; D056945:Hep G2 Cells; D022781:Hepatocytes; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D007511:Ischemia / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D012436:S-Adenosylmethionine / Q000494:pharmacology* / Q000627:therapeutic use; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D000097642:GADD45 Proteins
chemical_list: D000943:Antigens, Differentiation; D000071193:Autophagy-Related Protein 7; D034741:RNA, Small Interfering; D012436:S-Adenosylmethionine; D016159:Tumor Suppressor Protein p53; C086470:GADD45B protein, human; D000097642:GADD45 Proteins; C495901:TP53 protein, human; C509349:ATG7 protein, human
keywords: GADD45β; S-adenosylmethionine; apoptosis; hepatocellular carcinoma; ischemia-hypoxia