title: COX-2 contributes to P-glycoprotein-mediated multidrug resistance via phosphorylation of c-Jun at Ser63/73 in colorectal cancer.
abstract: Cross-drug resistance in multidrug-resistant (MDR) cells, which overexpress P-glycoprotein (P-gp) encoded by the MDR1 gene, is a major impediment to successful chemotherapy for colorectal cancer. In the present study, drug-sensitive HCT8 and multidrug-resistant (vincristine, VCR) HCT8/V colorectal cancer cell lines were used to examine the role of c-Jun NH2-Terminal Kinase- (JNK) signaling pathway in P-gp-mediated MDR associated with Cyclo-oxygenase-2 (COX-2). The results showed that SP600125, a JNK inhibitor, and NS-398, a COX-2 inhibitor, significantly reduced the degree of MDR in HCT8/V cells. This was accompanied by a significant decrease in gene level of MDR1 and protein level of P-gp in HCT8/V cells. Notably, addition of a JNK inhibitor had no significant effect on the expression of COX-2 in both HCT8 and HCT8/V cells. Interestingly, inhibition of COX-2 activity by a chemical inhibitor or its silence by small interfering RNA significantly decreased the level of phosphorylated c-Jun at Ser63/73 in HCT8/V cells. In contrast, upregulation of COX-2 significantly increased the levels of P-gp and p-c-Jun at Ser63/73 in HCT8 cells, but not in HCT8/V cells. Moreover, the intracellular vincristine accumulation in HCT8/V cells significantly increased after inhibiting COX-2 and JNK activity. Taken together, our study has provided the first direct evidence that COX-2 contributes to P-gp-mediated multidrug resistance via phosphorylation of c-Jun at Ser63/73 in colorectal cancer cells.
authors.affiliation: Interventional Cancer Institute of Integrative Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Sui
authors.forename: Shoufeng
authors.initials: S
authors.lastname: Zhou
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Xuan
authors.initials: X
authors.lastname: Liu
authors.forename: Lihong
authors.initials: L
authors.lastname: Zhou
authors.forename: Peihao
authors.initials: P
authors.lastname: Yin
authors.forename: Zhongze
authors.initials: Z
authors.lastname: Fan
authors.forename: Qi
authors.initials: Q
authors.lastname: Li
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012694:Serine / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012694:Serine; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human