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ROS-mediated activation of AKT induces apoptosis via pVHL in prostate cancer cells

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Abstract

Reactive oxygen species (ROS) play a central role in oxidative stress, which leads to the onset of diseases, such as cancer. Furthermore, ROS contributes to the delicate balance between tumor cell survival and death. However, the mechanisms by which tumor cells decide to elicit survival or death signals during oxidative stress are not completely understood. We have previously reported that ROS enhanced tumorigenic functions in prostate cancer cells, such as transendothelial migration and invasion, which depended on CXCR4 and AKT signaling. Here, we report a novel mechanism by which ROS facilitated cell death through activation of AKT. We initially observed that ROS enhanced the expression of phosphorylated AKT (p-AKT) in 22Rv1 human prostate cancer cells. The tumor suppressor PTEN, a negative regulator of AKT signaling, was rendered catalytically inactive through oxidation by ROS, although the expression levels remained consistent. Despite these events, cells still underwent apoptosis. Further investigation into apoptosis revealed that expression of the tumor suppressor pVHL increased, and contains a target site for p-AKT phosphorylation. pVHL and p-AKT associated in vitro, and knockdown of pVHL rescued HIF1α expression and the cells from apoptosis. Collectively, our study suggests that in the context of oxidative stress, p-AKT facilitated apoptosis by inducing pVHL function.

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Acknowledgments

Research in this laboratory is supported, in part, by the National Institutes of Health Grants F31CA153908 (MAC), G12RR003062-22 (CVH) and P20MD002285 (CVH and VOM), and the American Association for the Advancement of Science (AAAS) Women’s International Research Collaborations (WIRC) for Minority Serving Institutions (MSIs), a National Science Foundation Grant.

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Authors and Affiliations

  1. Center for Cancer Research and Therapeutic Development, Clark Atlanta University, 223 James P. Brawley Drive, SW, Atlanta, GA, 30314, USA

    Mahandranauth A. Chetram, Danaya A. Bethea, Valerie A. Odero-Marah, Ayesha S. Don-Salu-Hewage, Kia J. Jones & Cimona V. Hinton

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  1. Mahandranauth A. Chetram
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  2. Danaya A. Bethea
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  6. Cimona V. Hinton
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Correspondence to Cimona V. Hinton.

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Chetram, M.A., Bethea, D.A., Odero-Marah, V.A. et al. ROS-mediated activation of AKT induces apoptosis via pVHL in prostate cancer cells. Mol Cell Biochem 376, 63–71 (2013). https://doi.org/10.1007/s11010-012-1549-7

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  • DOI: https://doi.org/10.1007/s11010-012-1549-7

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