Regulation of TRAIL-Induced Apoptosis by Transcription Factors

The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a newly identified member of the TNF family. Unlike many other members of the TNF family, TRAIL selectively induces apoptosis of tumor cells, but not normal cells. The mechanisms whereby TRAIL-induced apoptosis is regulated in various cell types are not clear. We report here that the peroxisome proliferator-activated receptor (PPAR)-gamma and nuclear factor (NF)-kappaB play distinct roles in regulating TRAIL-induced apoptosis. Activation of PPAR-gamma by its agonist pioglitazone significantly enhanced TRAIL-induced apoptosis. This was associated with inhibition of proliferation and cell cycle progression. On the other hand, inhibition of NF-kappaB by sulfasalazine also significantly enhanced TRAIL-induced apoptosis. These results strongly suggest that while transcription factor PPAR-gamma promotes TRAIL-induced apoptosis, NF-kappaB inhibits it. Thus, PPAR-gamma agonists and NF-kappaB inhibitors are potent enhancers of TRAIL-induced apoptosis.