Induction of DNA damage-inducible gene GADD45beta contributes to sorafenib-induced apoptosis in hepatocellular carcinoma cells.

Markers that could accurately predict responses to the general kinase inhibitor sorafenib are needed to better leverage its clinical applications. In this study, we examined a hypothesized role in the drug response for the growth arrest DNA damage-inducible gene 45β (GADD45β), which is commonly underexpressed in hepatocellular carcinoma (HCC) where sorafenib may offer an important new therapeutic option. The anticancer activity of sorafenib-induced GADD45β expression was tested in a panel of HCC cell lines and xenograft models. We found that GADD45β mRNA and protein expression were induced relatively more prominently in HCC cells that were biologically sensitive to sorafenib treatment. GADD45β induction was not found after treatment with either the mitogen-activated protein kinase-extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor U0126 or the Raf inhibitor ZM336372, suggesting that GADD45β induction by sorafenib was independent of Raf/MEK/ERK signaling activity. However, c-Jun NH2-terminal kinase (JNK) kinase activation occurred preferentially in sorafenib-sensitive cells. Small interfering RNA-mediated knockdown of GADD45βor JNK kinase limited the proapoptotic effects of sorafenib in sorafenib-sensitive cells. We defined the -339/-267 region in the GADD45β promoter containing activator protein-1 and SP1-binding sites as a crucial region for GADD45β induction by sorafenib. Together, our findings suggest that GADD45β induction contributes to sorafenib-induced apoptosis in HCC cells, prompting further studies to validate its potential value in predicting sorafenib efficacy.

Ou DL ，Shen YC ，Yu SL ，Chen KF ，Yeh PY ，Fan HH ，Feng WC ，Wang CT ，Lin LI ，Hsu C ，Cheng AL ... -  《-》

Induction of Bim expression contributes to the antitumor synergy between sorafenib and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase inhibitor CI-1040 in hepatocellular carcinoma.

Ou DL ，Shen YC ，Liang JD ，Liou JY ，Yu SL ，Fan HH ，Wang DS ，Lu YS ，Hsu C ，Cheng AL ... -  《-》

Growth arrest DNA damage-inducible gene 45 gamma expression as a prognostic and predictive biomarker in hepatocellular carcinoma.

Ou DL ，Shyue SK ，Lin LI ，Feng ZR ，Liou JY ，Fan HH ，Lee BS ，Hsu C ，Cheng AL ... -  《Oncotarget》

Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5.

Liu L ，Cao Y ，Chen C ，Zhang X ，McNabola A ，Wilkie D ，Wilhelm S ，Lynch M ，Carter C ... -  《CANCER RESEARCH》

The different induction mechanisms of growth arrest DNA damage inducible gene 45 β in human hepatoma cell lines.

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. 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. 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. GADD45β induction is a novel mechanism of SAMe-mediated hepatoprotection with p53 involvement.

Seewoo V ，Yang W ，Du H ，Wang J ，Lin A ，Shen B ，Peng C ，Li H ，Qiu W ... -  《-》