The Different Induction Mechanisms of Growth Arrest DNA Damage Inducible Gene 45 β in Human Hepatoma Cell Lines

Aims: Downregulation of the growth arrest and DNA damage-inducible gene 45 beta (GADD45 beta) has been verified to be specific to HCC and consistent with the degree of malignan-cy. The differences in induction mechanisms of GADD45 beta were investigated based on transcriptional regulation. Methods: Following our published data from S-adenosylmethionine (SAMe), oxaliplatin and sorafenib were further used to stimulate GADD45(3 expression in cultured HepG2 (p53 wild type) and Hep3B (p53 null) hepatoma cells in vitro. The different effects on cell viability, DNA synthesis and caspase activities were also measured. Results: Oxaliplatin and sorafenib could induce GADD45 beta in both HepG2 and Hep3B in a dose-dependent manner with rapid and direct cytotoxic effect. Transcriptional activity of NF-kappa B and E2F-1 were both enhanced by oxaliplatin and sorafenib. However, SAMe could only induce GADD45 beta in HepG2 through the NF-kappa B pathway, resulting in a slow and indirect cytotoxic effect. Although all three inducers could lead to a pronounced rise in caspase activities, only high concentration of SAMe could inhibit DNA synthesis as significantly as the chemo drugs. No apparent changes in GADD45 beta induction, promoter activity or cytotoxic effects were observed in Hep3B(+P53) when treated with oxaliplatin and sorafenib, while relatively significant changes occurred with SAMe. Conclusion: GADD45 beta induction is a novel mechanism of SAMe-mediated hepatoprotec-tion with p53 involvement. Copyright (C) 2012 S. Karger AG, Basel