Translational regulation of TRAIL sensitivity

Abstract

TNF-related apoptosis-inducing ligand (TRAIL) is a peptide that induces apoptosis to varying degrees in tumor cells. While TRAIL sensitivity in tumors has been linked to c-myc-and MEK/Erk-induced enhancement of caspase activation, our recent study identified a third input controlling TRAIL sensitivity, namely the Akt-mTOR pathway. We showed that instead of enhancing TRAIL sensitivity, Akt expression, acting through mTOR and the mTOR targets S6 kinase and elF-4E, selectively enhances translation of the anti-apoptotic protein FLIPS and confers TRAIL resistance. In this perspective article we will discuss the linkage of the Akt-mTOR pathway to other regulators of TRAIL sensitivity, its importance in controlling a broader range of apoptotic events, its utility in predicting TRAIL responsiveness, and its potential manipulation for therapeutic benefit. ©2006 Landes Bioscience.