Induction of DNA Damage-Inducible Gene GADD45β Contributes to Sorafenib-Induced Apoptosis in Hepatocellular Carcinoma Cells

Abstract

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 NH 2 -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. Cancer Res; 70(22); 9309-18. ©2010 AACR.

Integrated Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC) and Isobaric Tags for Relative and Absolute Quantitation (iTRAQ) Quantitative Proteomic Analysis Identifies Galectin-1 as a Potential Biomarker for Predicting Sorafenib Resistance in Liver Cancer*

“…The sorafenib-resistant HCC cell line, HuH-7 R , was established by long-term exposure of cells to sorafenib as previously reported (10).…”

“…R Cells-Resistant HuH-7 R cell lines were established previously (10). As shown in supplemental Fig.…”

Cyclin E1 Inhibition can Overcome Sorafenib Resistance in Hepatocellular Carcinoma Cells Through Mcl-1 Suppression

“…Tumor volume and body weight were recorded every 7 days. At the end of drug treatment, tumor samples were collected for Western blotting, immunohistochemical analysis, and a terminal deoxynucleotidyl transferasemediated dUTP nick end labeling (TUNEL) assay (25).…”

18β‐glycyrrhetinic acid inhibits hepatocellular carcinoma development by reversing hepatic stellate cell‐mediated immunosuppression in mice

“…9 It strongly inhibits different tumor cells including HCC cell proliferation and angiogenesis and induces apoptosis. Recent studies have suggested that sorafenib induced HCC cell apoptosis might be through induction of the growth arrest DNA damage-inducible gene 45b and an intrinsic mechanism where JNK-mediated PUMA up-regulation 47,48 Moreover, sorafenib was also reported to down-regulate the suppressive immune cell populations: Treg cells and myeloid-derived suppressor cells (MDSC) expression in a murine liver cancer model. 43 Another hot drug, mTOR pathways inhibitor, rapamycin as a single agent or in combination with other chemicals could inhibit tumor growth and angiogenesis in HCC in vitro and in vivo.…”