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Sodium selenite induces apoptosis by generation of superoxide via the mitochondrial-dependent pathway in human prostate cancer cells

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Abstract

Purpose

Studies have demonstrated that selenium supplementation reduces the incidence of cancer, particularly prostate cancer. Evidence from experimental studies suggests that apoptosis is a key event in cancer chemoprevention by selenium and reactive oxygen species play a role in induction of apoptosis by selenium compounds. The current study was designed to investigate the role of superoxide and mitochondria in selenite-induced apoptosis in human prostate cancer cells.

Methods

LNCaP cells were transduced with adenoviral constructs to overexpress four primary antioxidant enzymes: manganese superoxide dismutase (MnSOD), copper-zinc superoxide dismutase (CuZnSOD), catalase (CAT), or glutathione peroxidase 1 (GPx1). Cell viability, apoptosis, and superoxide production induced by sodium selenite were analyzed by the MTT assay, chemiluminescence, flow cytometry, western blot analysis, and Hoechst 33342 staining following overexpression of these antioxidant enzymes.

Results

Our study shows the following results: (1) selenite induced cancer cell death and apoptosis by producing superoxide radicals; (2) selenite-induced superoxide production, cell death, and apoptosis were inhibited by overexpression of MnSOD, but not by CuZnSOD, CAT, or GPx1; and (3) selenite treatment resulted in a decrease in mitochondrial membrane potential, release of cytochrome c into the cytosol, and activation of caspases 9 and 3, events that were suppressed by overexpression of MnSOD.

Conclusions

This study demonstrates that selenite induces cell death and apoptosis by production of superoxide in mitochondria and activation of the mitochondrial apoptotic pathway and MnSOD plays an important role in protection against prooxidant effects of superoxide from selenite. The data suggest that superoxide production in mitochondria is, at least in part, a key event in selenium-induced apoptosis in prostate cancer cells.

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Acknowledgments

We thank Dr. Jeanne Bourdeau-Heller for her technical assistance. This work was funded, in part, by grants from the National Cancer Institute (CA114281) and the Office of Research and Development, Biomedical Laboratory Research and Development Service, Department of Veterans Affairs.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53792, USA

    Nong Xiang, Rui Zhao & Weixiong Zhong

  2. Pathology and Laboratory Medicine Service, William S. Middleton Memorial Veterans Hospital, Madison, WI, 53705, USA

    Weixiong Zhong

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  1. Nong Xiang
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  2. Rui Zhao
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Correspondence to Weixiong Zhong.

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Xiang, N., Zhao, R. & Zhong, W. Sodium selenite induces apoptosis by generation of superoxide via the mitochondrial-dependent pathway in human prostate cancer cells. Cancer Chemother Pharmacol 63, 351–362 (2009). https://doi.org/10.1007/s00280-008-0745-3

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  • DOI: https://doi.org/10.1007/s00280-008-0745-3

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