An Inducible Pathway for Degradation of FLIP Protein Sensitizes Tumor Cells to TRAIL-induced Apoptosis *

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