Sodium Selenite Induces Apoptosis by Generation of Superoxide via the Mitochondrial-Dependent Pathway in Human Prostate Cancer Cells

Cancer Chemother Pharmacol. 2009 Jan;63(2):351-62. doi: 10.1007/s00280-008-0745-3. Epub 2008 Apr 1.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenoviridae / genetics
  • Apoptosis / drug effects*
  • Catalase / genetics
  • Catalase / metabolism
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cytosol / drug effects
  • Dose-Response Relationship, Drug
  • Glutathione Peroxidase / genetics
  • Glutathione Peroxidase / metabolism
  • Humans
  • Male
  • Membrane Potential, Mitochondrial / drug effects
  • Mitochondria / drug effects*
  • Prostatic Neoplasms* / enzymology
  • Prostatic Neoplasms* / metabolism
  • Prostatic Neoplasms* / pathology
  • Sodium Selenite / pharmacology*
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism
  • Superoxides / metabolism*
  • Time Factors

Substances

  • Superoxides
  • Catalase
  • Glutathione Peroxidase
  • Superoxide Dismutase
  • Sodium Selenite