title: Homeostatic housecleaning effect of selenium: evidence that noncytotoxic oxidant-induced damage sensitizes prostate cancer cells to organic selenium-triggered apoptosis.
abstract: The anti-cancer activity of organic selenium has been most consistently documented at supra-nutritional levels at which selenium-dependent, antioxidant enzymes are maximized in both expression and activity. Thus, there is a strong imperative to identify mechanisms other than antioxidant protection to account for selenium's anti-cancer activity. In vivo work in dogs showed that dietary selenium supplementation decreased DNA damage but increased apoptosis in the prostate, leading to a new hypothesis: Organic selenium exerts its cancer preventive effect by selectively increasing apoptosis in DNA-damaged cells. Here, we test whether organic selenium (methylseleninic acid; MSA) triggers more apoptosis in human and canine prostate cancer cells that have more DNA damage (strand breaks) created by hydrogen-peroxide (H₂O₂) at noncytotoxic doses prior to MSA exposure. Apoptosis triggered by MSA was significantly higher in H₂O₂-damaged cells. A supra-additive effect was observed--the extent of MSA-triggered apoptosis in H₂O₂-damaged cells exceeded the sum of apoptosis induced by MSA or H₂O₂ alone. However, neither the persistence of H₂O₂-induced DNA damage, nor the activation of mitogen-activated protein kinases was required to sensitize cells to MSA-triggered apoptosis. Our results document that selenium can exert a "homeostatic housecleaning" effect--a preferential elimination of DNA-damaged cells. This work introduces a new and potentially important perspective on the anti-cancer action of selenium in the aging prostate that is independent of its role in antioxidant protection.
authors.affiliation: Department of Nutrition Science, Purdue University, West Lafayette, IN; Center on Aging and the Life Course, Purdue University, West Lafayette, IN; Gerald P. Murphy Cancer Foundation, West Lafayette, IN.
authors.forename: Emily C
authors.initials: EC
authors.lastname: Chiang
authors.forename: David G
authors.initials: DG
authors.lastname: Bostwick
authors.forename: David J
authors.initials: DJ
authors.lastname: Waters
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects; D004285:Dogs; D005047:Etoposide / Q000494:pharmacology; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D009153:Mutagens / Q000494:pharmacology; D016566:Organoselenium Compounds / Q000494:pharmacology*; D016877:Oxidants / Q000494:pharmacology; D011471:Prostatic Neoplasms; D009353:Zinostatin / Q000494:pharmacology
chemical_list: D016588:Anticarcinogenic Agents; D009153:Mutagens; D016566:Organoselenium Compounds; D016877:Oxidants; D005047:Etoposide; D009353:Zinostatin; C008493:methylselenic acid; D006861:Hydrogen Peroxide
keywords: cell fate; chemoprevention; damage response; oxidative stress