title: Quercetin sensitizes pancreatic cancer cells to TRAIL-induced apoptosis through JNK-mediated cFLIP turnover.
abstract: 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.
authors.affiliation: Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 138-736, South Korea.
authors.forename: Ji Hye
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 138-736, South Korea.
authors.forename: Min Joo
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: Department of Biomedical Sciences and Department of Pharmacology, Cell Dysfunction Research Center (CDRC), University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Kyung-Chul
authors.initials: KC
authors.lastname: Choi
authors.affiliation: Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 138-736, South Korea; Asan Institute for Life Sciences, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea. Electronic address: jaekson@amc.seoul.kr.
authors.forename: Jaekyoung
authors.initials: J
authors.lastname: Son
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D058990:Molecular Targeted Therapy; D010190:Pancreatic Neoplasms / Q000473:pathology*; D059748:Proteolysis / Q000187:drug effects; D011794:Quercetin / Q000494:pharmacology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D053221:TNF-Related Apoptosis-Inducing Ligand; D011794:Quercetin; D048031:JNK Mitogen-Activated Protein Kinases; D020169:Caspases
keywords: JNK; Pancreatic cancer; Quercetin; TRAIL; cFLIP