Tumor necrosis factor-related apoptosis-inducing
ligand (TRAIL) is a promising
anticancer agent that can selectively kill
cancer cells. Nonetheless, many
cancers are resistant to TRAIL, and the molecular mechanisms of TRAIL resistance in
cancer, particularly
pancreatic cancer, are still unclear. In this study, we tested the hypothesis that
quercetin, a
flavonoid, induces apoptosis in TRAIL-resistant
pancreatic cancer cells. Although
quercetin alone had no significant cytotoxic effect, when combined with TRAIL, it promoted TRAIL-induced apoptosis that required mitochondrial outer membrane permeabilization. A BH3-only
protein BID knockdown dramatically attenuated TRAIL/
quercetin-induced apoptosis. The expression levels of cellular FLICE-like inhibitory
protein (cFLIP) decreased in a dose-dependent manner in the presence of
quercetin, and overexpression of cFLIP was able to robustly rescue
pancreatic cancer cells from TRAIL/
quercetin-induced apoptosis. Additionally,
quercetin activated
c-Jun N-terminal kinase (JNK) in a dose-dependent manner, which in turn induced the proteasomal degradation of cFLIP, and JNK activation also sensitized
pancreatic cancer cells to TRAIL-induced apoptosis. Thus, our results suggest that
quercetin induces TRAIL-induced apoptosis via JNK activation-mediated cFLIP turnover.