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RETRACTED ARTICLE: Hypoxia-associated p38 mitogen-activated protein kinase-mediated androgen receptor activation and increased HIF-1α levels contribute to emergence of an aggressive phenotype in prostate cancer

Oncogene volume 28, pages 1248–1260 (2009)Cite this article

This article was retracted on 19 May 2022

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Abstract

Androgen receptor (AR) signaling is involved in the development and progression of prostate cancer. Tumor microvasculature contributes to continual exposure of prostate cancer cells to hypoxia–reoxygenation, however, the role of hypoxia–reoxygenation in prostate cancer progression and modulation of AR signaling is not understood. In this study, we evaluated the effects of hypoxia–reoxygenation in LNCaP cells, a line of hormone responsive human prostate cancer cells. Our results demonstrate that hypoxia–reoxygenation resulted in increased survival, higher clonogenicity and enhanced invasiveness of these cells. Moreover, hypoxia–reoxygenation was associated with an increased AR activity independent of androgens as well as increased hypoxia inducible factor (HIF-1α) levels and activity. We also observed that the activation of p38 mitogen-activated protein (MAP) kinase pathway was an early response to hypoxia, and inhibition of p38 MAP kinase pathway by variety of approaches abolished hypoxia–reoxygenation induced increased AR activity as well as increased survival, clonogenicity and invasiveness. These results demonstrate a critical role for hypoxia-induced p38 MAP kinase pathway in androgen-independent AR activation in prostate cancer cells, and suggest that hypoxia–reoxygenation may select for aggressive androgen-independent prostate cancer phenotype.

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Acknowledgements

Supported in part by NIH/NCI-P20 CA103680-Schwartz/Byers Program PI's (H Koul, Pilot-Project PI), Student Cancer Research Fellowship Program (H Koul, Preceptor), University of Colorado Cancer Center and Department of Surgery—School of Medicine Academic Enrichment Funds (H Koul). We thankfully acknowledge service provided by University of Colorado Cancer Center Flow Cytometry Core. We thank Dr Andrew Kung (Dana-Faber Cancer Institute, Boston, MA, USA) for 3 × HRE luciferase plasmid, Dr Magnus Essand (Uppsala University, Sweden) for AR responsive Luciferase Vector PSAe/TARPp and Professor Matthias Gaestel (Institute of Biochemistry, Medical School, Hannover, Germany) for MK2 expression plasmids.

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Authors and Affiliations

  1. Division of Urology, Department of Surgery, Signal Transduction and Molecular Urology Laboratory-Program in Urosciences, School of Medicine, University of Colorado at Denver and Health Sciences Center, Aurora, CO, USA

    L Khandrika, R Lieberman, S Koul, B Kumar, P Maroni, R Chandhoke, R B Meacham & H K Koul

  2. University of Colorado Comprehensive Cancer Center, University of Colorado at Denver and Health Sciences Center, Aurora, CO, USA

    P Maroni, R B Meacham & H K Koul

  3. Denver Veterans Administrative Medical Center, University of Colorado at Denver and Health Sciences Center, Aurora, CO, USA

    H K Koul

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  1. L Khandrika
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Correspondence to H K Koul.

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Khandrika, L., Lieberman, R., Koul, S. et al. RETRACTED ARTICLE: Hypoxia-associated p38 mitogen-activated protein kinase-mediated androgen receptor activation and increased HIF-1α levels contribute to emergence of an aggressive phenotype in prostate cancer. Oncogene 28, 1248–1260 (2009). https://doi.org/10.1038/onc.2008.476

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