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.

Sensitivity of Gastric Cancer Cells to Chemotherapy Drugs in Elderly Patients and Its Correlation with Cyclooxygenase-2 Expression

“…The studies have also confirmed that COX-2 can modulate the expression of GST-π, P-gp and TopoIIα (Segawa et al, 2008;Sui et al, 2011). The results in this study displayed that in observation group, COX-2 expression in cancer tissue had a significantly-positive correlation with GST-π and P-gp, but a negative correlation with TopoIIα.…”

Galectin‑3 rs4652 A>C polymorphism is associated with the risk of gastric carcinoma and P‑glycoprotein expression level

“…Association between rs4652 genotypic distributions and P-glycoprotein expression. (31). Therefore, the increased expression of the Pgp protein can be used as a marker for multi-drug resistance.…”

The network of P-glycoprotein and microRNAs interactions

“…In fact, the contribution of cyclooxygenase (COX2) to P-gp mediated drug resistance, via phosphorylation of c-Jun, has been described. 23 Moreover, the activation role of some p53 mutants on P-gp promoter has been reported 24,25 as well as the identification of P-gp as a target of transactivation by the bcatenin complex=T cell factor 4, which is thought to be the basis of tumorigenesis in colorectal cancer 26 ( Fig. 1-panel a).…”

“…siRNAs targeting MDR-1 in cells suppressed P-gp expression, reverting multidrug resistance in colon cancer cells. [21][22][23][24]26 Renal Cancer P-gp transcripts or protein identified in normal renal proximal tubules and in the majority of renal cell carcinoma samples indicated that this efflux pump is implicated in both intrinsic and acquired resistance. [27][28][29][30][31][32][33] Liver Cancer Overexpression of P-gp (but not MRP1) mainly contributes to the MDR of SMMC-7721/ADM cells.…”