Hepatocellular carcinoma (HCC) is one of leading causes of cancer-related death with a heterogeneous patient demographic and divergent pathogenic pathways. Sorafenib is the first effective drug approved for the treatment of HCC. Although it is known that sorafenib promotes apoptosis of HCC cells, the underlying mechanism remains largely obscure. Here we report that sorafenib down-regulates protein expression of the anti-apoptotic protein c-IAP1 in a time- and dose-dependent manner in HCC cells in vitro and in vivo. Furthermore, we demonstrate that sorafenib represses c-IAP1 levels without altering its transcription or protein stability. Instead, sorafenib attenuates c-IAP1 translation by targeting the internal ribosome entry site (IRES) within the c-IAP1 mRNA. Finally, ectopic expression of c-IAP1 alleviates sorafenib induced cancer cell apoptosis. In conclusion, our data highlight a previously unidentified pathway that contributes to sorafenib mediated HCC cell apoptosis and as such provide novel mechanistic insight into the rational use of sorafenib in treating HCC. (C) 2012 Elsevier Inc. All rights reserved.