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-γ. We hypothesized that co-treatment using TWEAK with other pro- apoptosis 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 (ΔΨ m ) that were more marked with combined treatment. ROS, ΔΨ m and cell death were partially normalized by the antioxidant N-acetylcysteine. TWEAK induced nuclear factor-kappa B activation, which was attenuated by 15d-PGJ 2 . 15d-PGJ 2 reduced the expression of the anti-apoptotic proteins BCL-X L and MCL-1, 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 may have chemotherapeutic utility as an apoptosis-enhancing agent. The tumor necrosis factor family consists of at least 18 members that exert a broad range of biological functions, including regulation of inflammation, cell proliferation, differentiation and death (1, 2). Among them TNFα