Research Papers:

GADD45β induction by S-adenosylmethionine inhibits hepatocellular carcinoma cell proliferation during acute ischemia-hypoxia

Ding Ma _, Baiyong Shen, Varun Seewoo, Hui Tong, Weiping Yang, Xi Cheng, Zhijian Jin, Chenghong Peng and Weihua Qiu

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Oncotarget. 2016; 7:37215-37225. https://doi.org/10.18632/oncotarget.9295

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Ding Ma1,*, Baiyong Shen1,*, Varun Seewoo1,*, Hui Tong2, Weiping Yang1, Xi Cheng1, Zhijian Jin1, Chenghong Peng1, Weihua Qiu1

1Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

2Department of Surgery, Huadong Hospital, Shanghai, China

*These authors have contributed equally to this work

Correspondence to:

Weihua Qiu, e-mail: [email protected]

Chenghong Peng, e-mail: [email protected]

Keywords: hepatocellular carcinoma, S-adenosylmethionine, ischemia-hypoxia, GADD45β, apoptosis

Received: March 02, 2016    Accepted: April 26, 2016    Published: May 11, 2016


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.

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