Targeting G-protein coupled receptor-related signaling pathway in a murine xenograft model of appendiceal pseudomyxoma peritonei.

ABSTRACT

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.