Sorafenib (BAY 43-9006) downregulates survivin protein level by inhibition of translation in human NSCLC cells

Eun-Sung Kim, Sung-Keum Seo, Hyeon-Ok Jin, In-Chul Park
Korea Institute of Radiological and Medical Sciences, Seoul, Korea, Republic of

Sorafenib (BAY 43-9006, Nexavar®) has a broad spectrum activity against tyrosin kinase including c-Raf , vascular endothelial growth factor receptor, and platelet-derived growth factor receptor. However, the mechanism(s) of action sorafenib remains incompletely defined. In the present study, the effect of sorafenib on the antiapoptotic protein survivin, an inhibitor of apoptosis protein family, were examined in various NSCLC cell lines. Sorafenib markedly caused a down-regulation of survivin protein expression level in lung cancer cells. Sorafenib treatment did not significantly affect the levels of other IAP family, including XIAP, cIAP1 and cIAP2. To determine whether survivin was downregulated at the transcriptional level, we measured mRNA in lung cancer cells after treated with sorafenib assessed by RT-PCR. The result shows that sorafenib did not alter the survivin mRNA expression level. To further examine the effects of sorafenib on survivin downregulation, 26S proteasome in lung cancer cells was blocked by MG132; and the protein levels of survivin were examined after 24hr in the absence or presence of sorafenib. MG132 did not recover the sorafenib-induced downregulation of survivin. Therefore, survivin downregulation by sorafenib occurred in a 26S proteasome-independent manner. These results suggest that sorafenib-induced survivin downregulation is mediated by inhibition of translation initiation in human NSCLC cells.