Targeting G-protein coupled receptor-related signaling pathway in a murine xenograft model of appendiceal pseudomyxoma peritonei
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Ashok K. Dilly1, Brendon D. Honick1, Yong J. Lee1,2, Zong S. Guo1, Herbert J. Zeh1, David L. Bartlett1 and Haroon A. Choudry1
1Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh PA 15232, USA
2Department of Pharmacology and Chemical Biology, University of Pittsburgh Medical Center, Pittsburgh PA 15232, USA
Haroon A. Choudry, email: [email protected]
Keywords: MUC2; xenograft; pseudomyxoma peritonei; COX-2; CREB
Received: August 31, 2017 Accepted: October 17, 2017 Published: November 06, 2017
Cancer cells aberrantly express mucins to enhance their survival. Relative chemoresistance of appendiceal pseudomyxoma peritonei (PMP) is attributed to abundant extracellular mucin 2 (MUC2) protein production. We hypothesized that simultaneous MUC2 inhibition and apoptosis induction would be effective against mucinous tumors. In vitro studies were conducted using LS174T cells (MUC2-secreting human colorectal cancer cells), PMP explant tissue, and epithelial organoid cultures (colonoids) derived from mucinous appendix cancers. In vivo studies were conducted using murine intraperitoneal patient-derived xenograft model of PMP. We found COX-2 over-expression in PMP explant tissue, which is known to activate G-protein coupled EP4/cAMP/PKA/CREB signaling pathway. MUC2 expression was reduced in vitro by small molecule inhibitors targeting EP4/PKA/CREB molecules and celecoxib (COX-2 inhibitor), and this was mediated by reduced CREB transcription factor binding to the MUC2 promoter. While celecoxib (5–40 μM) reduced MUC2 expression in vitro in a dose-dependent fashion, only high-dose celecoxib (≥ 20 μM) decreased cell viability and induced apoptosis. Chronic oral administration of celecoxib decreased mucinous tumor growth in our in vivo PMP model via a combination of MUC2 inhibition and induction of apoptosis. We provide a preclinical rationale for using drugs that simultaneously inhibit MUC2 production and induce apoptosis to treat patients with PMP.
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