Abstract 1537: Dual-specificity phosphatase-2 negatively controls chemoresistance in cancer cells

Abstract The limitation of clinical cancer therapy is due to a lot of mechanisms including influence of uptake, metabolism and export of drug from a single cell that contribute to drug resistance at the cellular level. In addition, tumor microenvironment also plays an important role in promoting drug resistance. For example, hypoxia has been reported to induce drug resistance by modulating expression of numerous genes. It has been shown that targeting individual hypoxia-regulated gene decreases drug resistance. However, it is an inefficient and infeasible way to target individual drug resistance-related genes one by one. Here we show that extracellular signal-regulated kinase 1/2 (ERK1/2), a survival pathway, is activated by hypoxia and blocking ERK1/2 pathway attenuates hypoxia-induced drug resistance. Furthermore, we also find that dual-specificity phosphatase-2 (DUSP2), a nuclear phosphatase that controls activity of ERK1/2, is inhibited by hypoxia through transcriptional repression. Inhibition of DUSP2 results in prolonged activation of ERK and increasing cell survival. Overexpression of DUSP2 causes cell apoptosis under normoxia and decreases hypoxia-induced drug resistance while stable knockdown DUSP2 increases drug resistance under normoxia. Moreover, re-expression of DUSP2 under hypoxia blocks tumor growth and enhances drug sensitivity in xenografted mice. Taken together, we identified an important role of DUSP2 involving hypoxia-mediated drug resistance and targeting DUSP2 might provide more specific and efficient way for cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1537.