Recombinant Thrombomodulin Has Anti-tumor Effects and Enhances the Effects of Gemcitabine for Pancreatic Cancer Through G-protein Coupled Receptor 15.

Abstract

Thrombomodulin™ has cytoprotective and anti-inflammatory function by interacting with G-protein coupled receptor 15 (GPR15). Recombinant TM (rTM), which comprises the extracellular regions of TM, is approved for treatment of disseminated intravascular coagulation. We investigated the anti-tumor effect of rTM for pancreatic ductal adenocarcinoma (PDAC) through GPR15. We evaluated the expression of GPR15 in human PDAC cell lines and the anti-tumor effect and signals of rTM in vitro and in vivo. To test whether GPR15 would be responsible for the inhibition of cell proliferation by rTM, we evaluated the cell viability of the GPR15 knockdown cells treated with rTM using GPR15-targeting siRNA. We identified PDAC cell lines with GPR15 expression and discovered that rTM inhibited tumor growth and enhanced the effects of gemcitabine (GEM) for the PDAC cell line in a GPR15-dependent manner. Furthermore, we showed that rTM inhibited nuclear factor-kappaB (NF-[Formula: see text]B) and extracellular signal-regulated kinase (ERK) activation through interactions with GPR15. We demonstrated that rTM had anti-tumor effect and enhancement of cytotoxic effect of GEM for PDAC cells by inhibiting NF-[Formula: see text]B and ERK activation via GPR15 and suggest that rTM is a potential therapeutic option for PDAC.