Abstract 3083: Dual-specificity phosphatase-2 (DUSP2) negatively control cyclooxygenase-2 (COX-2) expression in cancer cells

Abstract

Abstract Cyclooxygenase-2 (COX-2), an inducible form of cyclooxygenase, plays a crucial role in the development of cancer via its enzymatic product, prostaglandin E2 (PGE2). Clinical studies reveal that COX-2 is overexpressed in numerous types of cancers, and is associated with increase of angiogenesis, metastasis, and drug resistance. Although nonsteroidal anti-inflammatory drugs, COX-2 inhibitors, have been used for cancer therapy; they have serious side effects in many aspects. Therefore, to explore the underlying mechanism of COX-2 overexpression during cancer progression is critical for developing more efficient and safer way to block COX-2 function. Previously, we have found that the expression of dual-specificity phosphatase-2 (DUSP2), a MAPK-specific phosphatase, is markedly reduced in many kinds of cancers. Here, we identified that COX-2 was a potential downstream target gene of DUSP2. In vitro studies demonstrate that knockdown of DUSP2 significantly increases COX-2 expression and PGE2 production while overexpression of DUSP2 reduces those in cancer cells. Xenografted mouse study further reveals that levels of DUSP2 are reduced during cancer development, which is inversely correlated with COX-2 expression. Re-expression of DUSP2 during tumor progression inhibits COX-2 expression and suppresses tumor growth while knockdown of DUSP2 increases COX-2 expression and enhances tumor growth. These results implied that COX-2 overexpression was due to loss of DUSP2 expression in cancer. Furthermore, we found that hypoxia represses DUSP2 expression resulting in COX-2 overexpression. Taken together, we have demonstrated for the first time that aberrant expression of COX-2 during tumor development is regulated by hypoxia-mediated DUSP2 downregulation. Our data also suggest that DUSP2 is a good molecular target for cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3083. doi:1538-7445.AM2012-3083