An inducible pathway for degradation of FLIP protein sensitizes tumor cells to TRAIL-induced apoptosis

TRAIL (Apo2 ligand) is a member of the tumor necrosis factor (TNF) family of cytokines that induces apoptosis. Because TRAIL preferentially kills tumor cells, sparing normal tissues, interest has emerged in applying this biological factor for cancer therapy in humans. However, not all tumors respond to TRAIL, raising questions about resistance mechanisms. We demonstrate here that a variety of natural and synthetic ligands of peroxisome proliferator-activated receptor-gamma (PPARgamma) sensitize tumor but not normal cells to apoptosis induction by TRAIL. PPARgamma ligands selectively reduce levels of FLIP, an apoptosis-suppressing protein that blocks early events in TRAIL/TNF family death receptor signaling. Both PPARgamma agonists and antagonists displayed these effects, regardless of the levels of PPARgamma expression and even in the presence of a PPARgamma dominant-negative mutant, indicating a PPARgamma-independent mechanism. Reductions in FLIP and sensitization to TRAIL-induced apoptosis were also not correlated with TNF-kappaB, further suggesting a novel mechanism. PPARgamma modulators induced ubiquitination and proteasome-dependent degradation of FLIP, without concomitant reductions in FLIP mRNA. The findings suggest the existence of a pharmacologically regulated novel target of this class of drugs that controls FLIP protein turnover, and raise the possibility of combining PPARgamma modulators with TRAIL for more efficacious elimination of tumor cells through apoptosis.