Abstract
The platinum-based chemotherapeutic agent, oxaliplatin, is used to treat advanced colorectal cancer (CRC). Unfortunately, nearly all patients acquire resistance to oxaliplatin after long-term use, limiting its therapeutic efficacy. Since COX-2 and PGE2 signaling can impact colon cancer cell proliferation and survival, we examined how this pathway was affected in an oxaliplatin resistant colon cancer cell line. PGE2 levels were significantly elevated in oxaliplatin-resistant HT29 cells (OXR) compared to naïve parental HT29 cells (PAR). This increase was associated with elevated COX-2 (17.9-fold; P = 0.008) and reduced 15-hydroxyprostaglandin dehydrogenase (2.9-fold; P < 0.0001) expression. RNAi knockdown of microsomal prostaglandin E synthase-1, the rate-limiting enzyme in PGE2 synthesis, sensitized OXR cells to oxaliplatin. Downstream effects of PGE2 in OXR cells were also examined. Selective inhibition of the EP4 PGE2 receptor by the small molecule inhibitor, L-161,982 enhanced oxaliplatin-induced apoptosis in OXR cells. L-161,982 also reduced expression of the colonic stem cell markers, CD133 and CD44, and inhibited tumor sphere formation. The accumulation of intracellular reactive oxygen species (ROS), a key component of oxaliplatin cytotoxicity, was significantly increased by EP4 inhibition (2.4 -fold; P < 0.0001). Overall, our findings uncover an important role for the COX-2/PGE2/EP4 signaling axis in oxaliplatin resistance via regulation of oxidative stress.
Highlights
Prostaglandin E2 (PGE2) levels were significantly elevated in oxaliplatin-resistant HT29 cells (OXR) compared to naïve parental HT29 cells (PAR)
To determine whether PGE2 metabolism is altered in the oxaliplatin-resistant cells, we measured the levels of PGE2 in the media from the parental PAR cells and OXR cells
The increase of COX-2 and microsomal prostaglandin E synthase-1 (mPGES-1) expression levels were not observed in oxaliplatin-resistant cell line RKO OXR in comparison to the parental (RKO PAR) cells, despite www.nature.com/scientificreports cells
Summary
PGE2 levels were significantly elevated in oxaliplatin-resistant HT29 cells (OXR) compared to naïve parental HT29 cells (PAR) This increase was associated with elevated COX-2 (17.9-fold; P = 0.008) and reduced 15-hydroxyprostaglandin dehydrogenase (2.9-fold; P < 0.0001) expression. Www.nature.com/scientificreports studies have shown that targeting PGE2 synthesis enhances the response to conventional and targeted chemotherapies[19,20,21], and drug combinations with COX inhibitors have been shown to overcome chemo-resistance found in bladder and metastatic breast cancers[22,23,24]. Our findings uncover an important role for the COX-2/PGE2/EP4 signaling axis in chemoresistance, in part through regulating the cellular redox status These studies provide the basis for further investigation into targeting EP4 as an adjuvant therapy for increasing oxaliplatin efficacy in CRC patients
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