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

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.

The subcellular distribution of MnSOD alters during sodium selenite-induced apoptosis

“…At the same time, MnTMPyP could inhibit cytochrome c release from mitochondria and the activation of caspase-9, -3 induced by 20 μM sodium selenite. Xiang et al also reported that the overexpression of MnSOD could suppress selenite-induced mitochondrial membrane potential decrease and meanwhile inhibit the release of cytochrome c from mitochondria to cytosol (19). Combined together, these results indicate that the alteration of subcellular localization of MnSOD is likely a primary effect of sodium selenite treatment and not a consequent event of apoptosis.…”

“…Previous studies have demonstrated that the superoxide production in mitochondria is a key event during selenite-induced apoptosis process (18)(19)(20)(21). However, the molecular mechanism of how sodium selenite triggers the accumulation of superoxide remains to be determined.…”

Upregulation of manganese superoxide dismutase (SOD2) is a common pathway for neuroendocrine differentiation in prostate cancer cells

“…Interestingly, neither melatonin nor silibinin are able to induce cell death which makes a difference in the outcome triggered by other antioxidants. 42,43 On the contrary, both antioxidants redirect cells toward a transdifferentiation process that matches a NE-like phenotype.…”

Sodium Selenite Inhibits Proliferation of Gastric Cancer Cells by Inducing SBP1 Expression

“…A large body of evidence has recently demonstrated the protective role of selenium against several major types of cancers including gastric cancer (Liu and Russell 2008;Lee et al 2011). For example, several studies have reported that sodium selenite induces apoptosis in human osteosarcoma, prostate cancer and leukemia (Cao et al 2006;Xiang et al 2009;Chen et al 2012). However, the precise mechanism by which sodium selenite exerts an inhibitory effect on gastric cancer is unclear.…”