Suppression of dual-specificity phosphatase–2 by hypoxia increases chemoresistance and malignancy in human cancer cells
Shih-Chieh Lin, … , Shao-Chieh Lin, Shaw-Jenq Tsai
Shih-Chieh Lin, … , Shao-Chieh Lin, Shaw-Jenq Tsai
Published April 1, 2011
Citation Information: J Clin Invest. 2011;121(5):1905-1916. https://doi.org/10.1172/JCI44362.
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Research Article Oncology

Suppression of dual-specificity phosphatase–2 by hypoxia increases chemoresistance and malignancy in human cancer cells

Abstract

Hypoxia inducible factor–1 (HIF-1) is the master transcriptional regulator of the cellular response to altered oxygen levels. HIF-1α protein is elevated in most solid tumors and contributes to poor disease outcome by promoting tumor progression, metastasis, and resistance to chemotherapy. To date, the relationship between HIF-1 and these processes, particularly chemoresistance, has remained largely unexplored. Here, we show that expression of the MAPK-specific phosphatase dual-specificity phosphatase–2 (DUSP2) is markedly reduced or completely absent in many human cancers and that its level of expression inversely correlates with that of HIF-1α and with cancer malignancy. Analysis of human cancer cell lines indicated that HIF-1α inhibited DUSP2 transcription, which resulted in prolonged phosphorylation of ERK and, hence, increased chemoresistance. Knockdown of DUSP2 increased drug resistance under normoxia, while forced expression of DUSP2 abolished hypoxia-induced chemoresistance. Further, reexpression of DUSP2 during cancer progression caused tumor regression and markedly increased drug sensitivity in mice xenografted with human tumor cell lines. Furthermore, a variety of genes involved in drug response, angiogenesis, cell survival, and apoptosis were found to be downregulated by DUSP2. Our results demonstrate that DUSP2 is a key downstream regulator of HIF-1–mediated tumor progression and chemoresistance. DUSP2 therefore may represent a novel drug target of particular relevance in tumors resistant to conventional chemotherapy.

Authors

Shih-Chieh Lin, Chun-Wei Chien, Jenq-Chang Lee, Yi-Chun Yeh, Keng-Fu Hsu, Yen-Yu Lai, Shao-Chieh Lin, Shaw-Jenq Tsai

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Figure 4

Reexpression of DUSP2 in cancer cells induces apoptosis and tumor regression.

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Reexpression of DUSP2 in cancer cells induces apoptosis and tumor regres...
(A) Representative Western blots showing levels of DUSP2-GFP, GFP, phosphorylated ERK, total ERK, HIF-1α, and HIF-1β in HeLa cells carrying the doxycycline-inducible DUSP2-GFP fusion gene (iDUSP2-GFP) or GFP alone (iGFP) cultured under normoxia or hypoxia in the presence (+) or (–) absence of doxycycline (Dox; 2 μg/ml) for 24 hours. (B) Induction of apoptosis in HeLa cells carrying the doxycycline-inducible DUSP2-GFP fusion gene or GFP alone cultured under normoxia or hypoxia in the presence or absence of doxycycline (2 μg/ml) for 24 hours. *P < 0.05 compared with group without doxycycline. (C) Growth curves of tumors with inducible DUSP2-GFP. Arrow indicates the day of addition of doxycycline. (D) Representative pictures showing tumors grown in mice (n = 5/group) inoculated with HeLa cells carrying inducible DUSP2-GFP genes without or with doxycycline treatment (left panel). Tumors are shown in situ (upper panel) and after removal (lower panel). Ruler shows centimeters. The average wet weights of tumors with inducible DUSP2-GFP on day 28 are shown in the right panel. (E) Representative pictures showing apoptotic cells (with brown nuclei) in tissue sections of xenografted tumors. Scale bar: 50 μm. (F and G) Growth curves, pictures of tumors, and average wet weights of tumors with inducible GFP. See legends to C and D. *P < 0.05 compared with groups without doxycycline treatment.