Abstract 2328: COX-2 induce mediated multidrug resistance by activating JNK signal transduction pathway in colorectal cancer

Abstract

Abstract Chemotherapy is an important therapeutic option for most cancer patients; however, drug resistance causes the failure of chemotherapy and becomes a major obstacle for successful chemotherapy. The overexpression of P-gp has been associated with the resistance to a wide range of anticancer drugs. In the present study, drug-sensitive and multidrug resistant MDR colon carcinoma cell lines were used to examine the role of JNK signaling pathway in P-gp-mediated MDR associated with COX-2. We have found that sp600125, a JNK inhibitor or NS-398, a COX-2 inhibitor, reduced the degree of MDR in MDR cells. This phenomenon was accompanied by a significant decrease in gene level of ABCB1 and protein level of P-gp in MDR cells. In contrast, addition of a JNK inhibitor had no significant effect on the expression of COX-2. Interestingly, inhibition of COX-2 activity led to a decreased level of p-c-Jun at Ser63/73 due to JNK activation. In addition, there is an overexpression of p-c-Jun in MDR cells transfected with recombinant vector pGL3-Basic-COX-2 promoter. Moreover, the intracellular vincristine accumulation significantly increased with treatment of sp600125, or NS-398. In conclusion, our study has provided the first direct evidence that COX-2 induced up-regulation of P-gp in MDR cells, which was associated with an enhanced activity of the c-Jun phosphorylation at Ser63/73. Our findings may facilitate the development of novel antitumor drugs that are more effective against both chemosensitive and MDR cells. Note: This abstract was not presented at the meeting. Citation Format: Qi Li, Hua Sui. COX-2 induce mediated multidrug resistance by activating JNK signal transduction pathway in colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2328. doi:10.1158/1538-7445.AM2014-2328