Abstract 3009: Targeting G-protein coupled receptor-related pathway in mucinous tumors

Abstract

Abstract Introduction: Pseudomyxoma peritonei (PMP) is an indolent malignancy characterized by excessive production of Mucin 2 (MUC2; a gel-forming secreted mucin). We have previously demonstrated mucinous tumor growth inhibition in a patient-derived murine xenograft model of PMP using the cyclooxygenase-2 (COX-2) inhibitor celecoxib. We evaluated the downstream mechanism for celecoxib-mediated MUC2-inhibition. Methods: In vitro and in vivo studies were conducted using MUC2-secreting LS174T cells, PMP explant tissue and a unique intraperitoneal patient-derived murine xenograft model of PMP (PDX model of PMP). Results: LS174T cells treated with COX-2 inhibitor celecoxib (5-20 μM) for 24 hours demonstrated a significant reduction in MUC2 protein expression measured by flow cytometric analysis. Similarly, in the PDX model of PMP chronic oral therapy with celecoxib (20 mg/kg/d) for 28 days significantly inhibited MUC2 protein expression in harvested tumor tissue. In the LS174T cells, PGE2 (a COX-2 product) induced MUC2 mRNA (real-time PCR) and protein expression (flow cytometry) and this was inhibited by the G-protein coupled-EP4 receptor inhibitor AH23848 as well as siRNA for CREB (cAMP response element-binding protein). Using chromatin immunoprecipitation assay in LS174T cells, we found that treatment with celecoxib or protein kinase A inhibitor (fragment 6-22 amide) significantly decreased CREB-transcription factor binding to the MUC2 promoter. Conclusions: These data suggest that celecoxib inhibits MUC2 expression via the G-protein coupled receptor/ cAMP/ Protein kinase A/ CREB pathway. Since activating G-protein (GNAS) mutations are commonly found in PMP and may be responsible for its unique mucinous phenotype, our data provide a rationale for targeting this pathway to control mucin production in this malignancy. Citation Format: Ashok K. Dilly, Yong J. Lee, Herbert J. Zeh, David L. Bartlett, Mohammad Haroon A. Choudry. Targeting G-protein coupled receptor-related pathway in mucinous tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3009.