Sorafenib, a multikinase inhibitor, is emerging as a promising targeted agent that may possess antitumor activity against a broad range of cancers. The mechanism by which sorafenib induces lung cancer cell death and apoptosis, however, is not understood. In the present study, we provide evidence that sorafenib acts through inhibition of mammalian target of rapamycin (mTOR) to down-regulate survivin and promote apoptotic cell death in human non-small cell lung cancer (NSCLC) cells. Sorafenib induced ATF4-mediated Redd1 expression, leading to mTOR inhibition-the upstream signal for down-regulation of survivin. Overexpression of survivin reduced sorafenib-induced apoptosis, whereas silencing survivin using small interfering RNA (siRNA) enhanced it, supporting the interpretation that down-regulation of survivin is involved in sorafenib-induced cell death in human NSCLC cells. Furthermore, sorafenib abolished the induction of survivin that normally accompanies IGF-1-stimulated mTOR activation. We further found that Redd1-induced mTOR down-regulation and ATF4/CHOP-induced expression of the TRAIL receptor DR5 associated with sorafenib treatment helped sensitize cells to TRAIL-induced apoptosis. Our study suggests that sorafenib mediates apoptotic cell death in human NSCLC cells through Redd1-induced inhibition of mTOR and subsequent down-regulation of survivin, events that are associated with sensitization to TRAIL-induced apoptotic cell death.
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