Date of Completion

5-3-2017

Embargo Period

4-27-2017

Keywords

Oxaliplatin; Chemoresistance; PGE2; Colorectal Cancer; Chemotherapy

Major Advisor

Dr. Daniel W. Rosenberg

Associate Advisor

Dr. Blanka Rogina

Associate Advisor

Dr. Kevin Claffey

Associate Advisor

Dr. Charles Giardina

Field of Study

Biomedical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

The platinum-base chemotherapeutic agent, oxaliplatin, is used to treat metastatic colorectal cancer (CRC). Unfortunately, nearly all patients develop acquired resistance to oxaliplatin after long-term use, limiting its therapeutic efficacy. Recent studies demonstrated synergistic inhibition of colorectal tumor growth by the combination of cyclooxygenase-2 (COX-2) inhibitors with oxaliplatin. The major COX-2 product, prostaglandin E2 (PGE2), has been implicated in colorectal carcinogenesis; however, it is unknown whether PGE2 affects colorectal tumor response to oxaliplatin. In this study, we investigated the potential role of PGE2 in oxaliplatin resistance of human colon cancer cells. Total secreted PGE2 levels were significantly increased in oxaliplatin-resistant HT29 cells (HT29 OXR) compared to parental cells. This was associated with increased COX-2 (18-fold, 95% confidence interval [CI]=10.71 to 24.35, P=0.008) and reduced 15-PGDH levels (2.18-fold, 95% confidence interval [CI]=0.45 to 0.64, P2. Knockdown of microsomal prostaglandin E synthase-1 (mPGES-1) sensitized HT29 OXR cells to oxaliplatin. Selective inhibition of PGE2 receptor (EP4 receptor) by L-161,982 treatment demonstrated a synergistic effect on oxaliplatin-induced cell apoptosis in OXR cells. L-161,982 also reduced the expression of colonic stem cell markers (CD133 and CD44) expression and tumor sphere formation by OXR cells. Furthermore, we identified that intracellular reactive oxygen species (ROS) accumulation, a key mechanism of oxaliplatin cytotoxicity, was significantly aggravated by EP4 inhibition. Addition of the antioxidant N-acetyl cysteine (NAC) reversed cellular ROS level in OXR cells and abolished the beneficial effect of EP4 blockade on oxaliplatin efficacy. Overall, our findings uncover an important role for PGE2/EP4 signaling in chemoresistance through regulation of oxidative stress and provide the rationale for targeting of EP4 signaling for increased oxaliplatin efficacy in CRC patients.

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