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 pro−apoptosis agents could sensitize death receptor−resistant colon cancer cells.

The effects of chemopreventive agents and TWEAK on cell death and apoptosis were determined using propidium iodide (PI) exclusion and M30 CytoDEATH.

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 (DeltaPsi(m)) that were more marked with combined treatment. ROS, DeltaPsi(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.

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.

PMID: 20150631 [PubMed − indexed for MEDLINE] Source: National Library of Medicine.