Transformation, translation and TRAIL: An unexpected intersection

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine with roles in tumor surveillance and tolerance. TRAIL selectively induces apoptosis in many malignant but not normal cells but the underlying cause for spontaneous TRAIL sensitivity remains elusive. We propose a novel hypothesis that links TRAIL sensitivity to translational arrest following stresses that inactivate eukaryotic elongation factor 2 (EF2). Affected cells experience a reduction in apoptotic threshold because, due to their short half-lives, levels of anti-apoptotic proteins quickly drop off once translation elongation is inhibited leaving pro-apoptotic proteins unchallenged. This change in protein profile renders affected cells sensitive to TRAIL-mediated apoptosis and places EF2 into the role of a sensor for cellular damage.