The multikinase inhibitor sorafenib induces p53 family-dependent apoptosis in hepatocellular carcinoma
The multikinase inhibitor sorafenib represents the first medical therapy to prolong survival of patients suffering from hepatocellular carcinoma. Here, we propose a new model of action for sorafenib via accumulation and activation of p53 and its family members p63 and p73. We have previously linked the p53 family to hepatocarcinogenesis, chemosensitivity and prognosis in hepatocellular carcinoma. Here, we show that sorafenib-induced apoptosis is p53-family-dependent and associated with classical downstream effects of this gene family. Blocking p53 family function using an siRNA approach leads to a substantial decrease in apoptosis and provides further evidence for the central involvement of the p53 family in sorafenib-induced cell death. Sorafenib induces expression of the death receptors TRAIL-Receptor 2 and CD95 and sensitizes tumor cells towards the extrinsic apoptosis pathway. In addition, sorafenib engages the intrinsic apoptosis pathway by decreasing anti-apoptotic Mcl-1 and Bcl-xL and inducing pro-apoptotic Bak, Bim, Puma and Noxa. By contrast, normal, primary human hepatocytes do not respond to sorafenib treatment via induction of apoptosis. Of clinical relevance, sorafenib induces activation of caspases and apoptosis in tumor tissue of patients with hepatocellular carcinoma. These data provide molecular mechanisms for the further development of novel therapeutic strategies for hepatocellular carcinoma based on the involvement of the p53 family members in apoptosis by sorafenib.