Abstract 399: Elevation of angiopoietin-like protein 4 by PGE2 and hypoxia promotes colorectal cancer progression

Abstract

Abstract Prostaglandin E2 (PGE2), the most abundant COX-2-derived prostaglandin found in colorectal cancers, promotes tumor cell proliferation and survival via multiple signaling pathways. However, the role of PGE2 in tumor hypoxia is not well understood. Here, we show that a synergistic effect of PGE2 and hypoxia on enhancing ANGPTL4 expression and that elevation of ANGPTL4 promotes colorectal cancer progression. PGE2 induces ANGPTL4 expression at both the mRNA and protein levels under hypoxic conditions. Moreover, hypoxia induces one of the prostaglandin receptors, known as EP1. Activation of EP1 enhances ANGPTL4 expression, whereas blockage of EP1 by its antagonist inhibits PGE2 induction of ANGPTL4 under hypoxic conditions. Over-expression of ANGPTL4 promotes cell proliferation and tumor growth in vivo. In addition, treatment with ANGPTL4 recombinant protein increases cancer cell proliferation through stimulating STAT1 activation. These findings are relevant to human disease since we found that the expression of ANGPTL4 and STAT1 are elevated in 50% of human colorectal cancers and there is a positive correlation between COX-2 and ANGPTL4 as well STAT1 expression in the specimens tested. These results indicate that PGE2 plays an important role in promoting cancer cellular adaptive response to hypoxia and cancer progression via ANGPTL4. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 399. doi:10.1158/1538-7445.AM2011-399