Journal Article

COX-2 contributes to P-glycoprotein-mediated multidrug resistance via phosphorylation of c-Jun at Ser63/73 in colorectal cancer

Hua Sui, Shoufeng Zhou, Yan Wang, Xuan Liu, Lihong Zhou, Peihao Yin, Zhongze Fan and Qi Li

in Carcinogenesis

Volume 32, issue 5, pages 667-675
Published in print May 2011 | ISSN: 0143-3334
Published online February 2011 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgr016
COX-2 contributes to P-glycoprotein-mediated multidrug resistance via phosphorylation of c-Jun at Ser63/73 in colorectal cancer

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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.

Journal Article.  6299 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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