The different induction mechanisms of growth arrest DNA damage inducible gene 45 β in human hepatoma cell lines.
OBJECTIVE
Downregulation of the growth arrest and DNA damage-inducible gene 45 β (GADD45β) has been verified to be specific to HCC and consistent with the degree of malignancy. The differences in induction mechanisms of GADD45β were investigated based on transcriptional regulation.


METHODS
Following our published data from S-adenosylmethionine (SAMe), oxaliplatin and sorafenib were further used to stimulate GADD45β 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 GADD45β in both HepG2 and Hep3B in a dose-dependent manner with rapid and direct cytotoxic effect. Transcriptional activity of NF-ĸB and E2F-1 were both enhanced by oxaliplatin and sorafenib. However, SAMe could only induce GADD45β in HepG2 through the NF-ĸB 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 GADD45β induction, promoter activity or cytotoxic effects were observed in Hep3B(+p53) when treated with oxaliplatin and sorafenib, while relatively significant changes occurred with SAMe.


CONCLUSIONS
GADD45β induction is a novel mechanism of SAMe-mediated hepatoprotection with p53 involvement.
Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Varun
V
Seewoo
Weiping
W
Yang
Hailei
H
Du
Jiayu
J
Wang
Andy
A
Lin
Baiyong
B
Shen
Chenghong
C
Peng
Hongwei
H
Li
Weihua
W
Qiu
D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D001557:Benzenesulfonates / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D050687:E2F1 Transcription Factor / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D010671:Phenylurea Compounds; D011725:Pyridines / Q000494:pharmacology; D012436:S-Adenosylmethionine / Q000494:pharmacology; D000077157:Sorafenib; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D000097642:GADD45 Proteins
D000943:Antigens, Differentiation; D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D020169:Caspases; D050687:E2F1 Transcription Factor; D016328:NF-kappa B; D009536:Niacinamide; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D010671:Phenylurea Compounds; D011725:Pyridines; D012436:S-Adenosylmethionine; D000077157:Sorafenib; D016159:Tumor Suppressor Protein p53; C086470:GADD45B protein, human; D000097642:GADD45 Proteins