PPARγ Ligand 15-Deoxy-delta 12,14-Prostaglandin J2 Sensitizes Human Colon Carcinoma Cells to TWEAK-induced Apoptosis

Background: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) has been shown to induce colon cancer cell apoptosis in the presence of interferon-gamma. We hypothesized that co-treatment using TWEAK with other proapoptosis agents could sensitize death receptor-resistant colon cancer cells. Materials and Methods: The effects of chemopreventive agents and TWEAK on cell death and apoptosis were determined using propidium iodide (PI) exclusion and M30 CytoDEATH. Results: We found that 15d-PGJ(2) sensitizes colon cancer cells to TWEAK-induced apoptosis. Caspase inhibition reduced 15d-PGJ(2)-, but not 15d-PGJ(2)+TWEAK-induced apoptosis. 15d-PGJ(2) promoted reactive oxygen species (ROS) production and dissipation of mitochondrial potential (Delta Psi(m)) that were more marked with combined treatment. ROS, Delta Psi(m) and cell death were partially normalized by the antioxidant N-acetylcysteine. TWEAK induced nuclear factor-kappa B activation, which was attenuated kv 15d-PGJ(2). 15d-PGJ(2) reduced the expression of the anti-apoptotic proteins BCL-X-L and MCL-I, while increasing BAX and translocation of cytochrome c and apoptosis-inducing factor. Conclusion: 15d-PGJ(2) sensitized cancer cells to TWEAK-induced apoptosis through an ROS-dependent cell death pathway and many have chemotherapeutic utility as an apoptosis-enhancing agent.