Abstract
Prostaglandin E(2) (PGE(2)), the most abundant COX-2-derived prostaglandin found in colorectal cancer, promotes tumor cell proliferation and survival via multiple signaling pathways. However, the role of PGE(2) in tumor hypoxia is not well understood. Here, we show a synergistic effect of PGE(2) and hypoxia on enhancing angiopoietin-like protein 4 (ANGPTL4) expression and that elevation of ANGPTL4 promotes colorectal cancer growth. PGE(2) induces ANGPTL4 expression at both the mRNA and protein levels under hypoxic conditions. Moreover, hypoxia induces one of the PGE(2) receptors, namely EP1. Activation of EP1 enhances ANGPTL4 expression, whereas blockage of EP1 by an antagonist inhibits PGE(2) induction of ANGPTL4 under hypoxic conditions. Importantly, overexpression of ANGPTL4 promotes cell proliferation and tumor growth in vitro and in vivo. In addition, treatment with ANGPTL4 recombinant protein increases colorectal carcinoma cell proliferation through effects on STAT1 signaling. The MAP kinase and Src pathways mediate ANGPTL4-induced STAT1 expression and activation. These results are relevant to human disease because we found that the expression of ANGPTL4 and STAT1 are elevated in 50% of human colorectal cancers tested and there is a positive correlation between COX-2 and ANGPTL4 as well STAT1 expression in colorectal carcinomas. Collectively, these findings suggest that PGE(2) plays an important role in promoting cancer cell proliferation via ANGPTL4 under hypoxic conditions.