Downregulation of amplified in breast cancer 1 contributes to the anti-tumor effects of sorafenib on human hepatocellular carcinoma

Abstract

Multi-kinase inhibitor sorafenib represents a major breakthrough in the therapy of advanced hepatocellular carcinoma (HCC). Amplified in breast cancer 1 (AIB1) is frequently overexpressed in human HCC tissues and promotes HCC progression. In this study, we investigated the effects of sorafenib on AIB1 expression and the role of AIB1 in anti-tumor effects of sorafenib. We found that sorafenib downregulated AIB1 protein expression by inhibiting AIB1 mRNA translation through simultaneously blocking eIF4E and mTOR/p70S6K/RP-S6 signaling. Knockdown of AIB1 significantly promoted sorafenib-induced cell death, whereas overexpression of AIB1 substantially diminished sorafenib-induced cell death. Downregulation of AIB1 contributed to sorafenib-induced cell death at least in part through upregulating the levels of reactive oxygen species in HCC cells. In addition, resistance to sorafenib-induced downregulation of AIB1 protein contributes to the acquired resistance of HCC cells to sorafenib-induced cell death. Collectively, our study implicates that AIB1 is a molecular target of sorafenib and downregulation of AIB1 contributes to the anti-tumor effects of sorafenib.