Constitutive activation of mitogen-activated protein kinase (MAPK) was reported in many cancers and is a critical factor for the growth of tumor. The function of MAPK signaling is controlled by the magnitude and duration of its phosphorylation. This highlights the importance of negative regulatory mechanisms in determining the output of MAPK pathway. Dual-specificity phosphatase 2 (DUSP2) is a nuclear-specific phosphatase, which is a potent inhibitor of MAP kinases. Hypoxia has been demonstrated to increase drug-resistance of cancer cells but the mechanisms is largely unknown. Here we demonstrate that hypoxia induces phosphorylation of MAPKs, especially ERK1/2 and P38, which results in increased drug-resistance. Further investigation reveals that elevated MAPK phosphorylation is due to downregulation of DUSP2 by hypoxia. Promoter activity, site-direct mutagenesis, and chromatin immunoprecipitation (ChIP) assays show that hypoxia suppresses DUSP2 expression is HIF-1\#945;-dependent and is controlled at the transcriptional level. Forced expression of DUSP2 under hypoxia inactivates MAPK and reverses hypoxia-mediated drug-resistance while knocking down DUSP2 under normoxia condition increases MAPK phosphorylation and cell survival. Taken together, these data demonstrate that DUSP2 is a critical factor contributing to hypoxia-mediated drug-resistance and provide a new avenue for investigating the progression and malignancy of cancers that constantly face hypoxia stress or with HIF-1\#945; elevation.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3389.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

American Association for Cancer Research
2009