AW00179 potentiates TRAIL-mediated death of human lung cancer H1299 cells through ROS-JNK-c-Jun-mediated up-regulation of DR5 and down-regulation of anti-apoptotic molecules.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) triggers apoptosis in tumor cells, but when used alone, it is not effective at treating TRAIL-resistant tumors. This resistance is challenging for TRAIL-based anti-cancer therapies. In this study, we found that 1-(4-trifluoromethoxy-phenyl)-3-[4-(5-trifluoromethyl-2,5-dihydro-pyrazol-1-yl)-phenyl]-urea (AW00179) sensitized human lung cancer H1299 cells to TRAIL-mediated apoptosis. Even in the absence of TRAIL, AW00179 strongly induced DR5 expression and decreased the expression of anti-apoptotic proteins, suggesting that the sensitizing effect of AW00179 on TRAIL-mediated apoptosis is due to increased levels of DR5 protein and decreased anti-apoptotic molecules. AW00179 also induced the activation of c-Jun and ERK; however, a pharmacologic inhibition study revealed that JNK-c-Jun signaling is involved in the induction of DR5 expression. In addition, reactive oxygen species (ROS) appear to be involved in AW00179 activity. In conclusion, AW00179 has the potential to sensitize H1299 cells to TRAIL-mediated apoptosis through two distinct mechanisms: ROS-JNK-c-Jun-mediated up-regulation of DR5, and down-regulation of anti-apoptotic molecules.