Abstract 1666: Suppression of cyclooxygenase-2 by dual-specificity phosphatase-2 ameilorates cancer malignancy

Aberrant production of cyclooxygenase-2 (COX-2) and COX-2-derived prostaglandin E2 (PGE2) have been demonstrated to contribute to tumor development and malignancy in many human cancers. However, the initiating factor responsible for maintaining high levels of COX-2 expression during cancer development remains enigmatic. We hypothesize that aberrant expression of COX-2 in cancer cells is initiated by hypoxia, a common phenomenon occurs in very early stage during cancer development. Herein, we present data demonstrating that levels of COX-2 in cancer cells are induced by hypoxia in a hypoxia-inducible factor-1α (HIF-1α)-dependent manner. Intriguingly, HIF-1α does not directly induce COX-2 promoter activity. In contrast, induction of COX-2 expression is mediated by HIF-1α-induced downregulation of dual specificity phosphatase-2 (DUSP-2), a MAPK-specific phosphatase. Forced expression of DUSP2 reduces the levels of COX-2, while knockdown of DUSP2 induces COX-2 expression in cancer cells. Moreover, depletion of DUSP2 also induces the expression of microsomal prostaglandin E synthase (mPGES) and consequently increases the production of PGE2. Further study reveals that re-induction of DUSP2 abolishes hypoxia-induced COX-2 expression and PGE2 production. To test the hypothesis that COX-2 mediates loss-of-DUSP2-induced tumorigenesis, a selective COX-2 inhibitor, NS-398, was used to block the function of COX-2 in the DUSP2-knockdown xenograft mouse model. Knockdown of DUSP2 markedly enhances tumor growth while treatment with NS-398 reverses loss-of-DUSP2-induced tumor development in vivo. Taken together, our data indicate that DUSP2, a negative regulator of COX-2, plays a critical tumor suppressive role and hypoxia, a common stress during cancer development, suppresses DUSP2 to initiate COX-2 overexpression and promote cancer progression. Our findings suggest that preventing DUSP2 from hypoxia-mediated downregulation or re-induction of DUSP2 during cancer development may represent a potential approach for cancer therapy. Citation Format: Yo-Hua Li, Shih-Chieh Lin, Shaw-Jenq Tsai. Suppression of cyclooxygenase-2 by dual-specificity phosphatase-2 ameilorates cancer malignancy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1666. doi:10.1158/1538-7445.AM2014-1666