102 STATINS INDUCE AUTOPHAGY BY INHIBITION OF GERANYLGERANYL BIOSYNTHESIS IN PROSTATE CANCER PC3 CELLS

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research I1 Apr 2010102 STATINS INDUCE AUTOPHAGY BY INHIBITION OF GERANYLGERANYL BIOSYNTHESIS IN PROSTATE CANCER PC3 CELLS Ankur Parikh, Chandra Childress, Qiong Lin, Daniel Rukstalis, and Wannian Yang Ankur ParikhAnkur Parikh More articles by this author , Chandra ChildressChandra Childress More articles by this author , Qiong LinQiong Lin More articles by this author , Daniel RukstalisDaniel Rukstalis More articles by this author , and Wannian YangWannian Yang More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.151AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES We have previously demonstrated that statins induce autophagy and cause rapid cell death in PC-3 cells. Autophagy, or “self-eating”, is a process responsible for intracellular material degradation, in which cytoplasmic components are engulfed by autophagosomes and delivered to lysosomes for degradation. Statins, a class of inhibitors of 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase, are commonly prescribed medications for treatment of hypercholesterolemia. Inhibition of HMG-CoA reductase halts biosynthesis of metabolites in mevalonate pathway that are required for production of cholesterol, ubiquinone (Coenzyme Q10), geranylgeranyl pyrophosphate and farnesyl pyrophosphate. To define which metabolite biosynthesis is involved in atorvastatin-induced autophagy, we performed rescue experiments by supplementation of various metabolites to cell culture medium. METHODS PC-3 cells were plated and treated with atorvastatin. Rescue experiments were performed with the addition of geranylgeraniol, farnesol, coenzyme Q 10, and squalene. Autophagic response was evaluated with Western Blot assays for expression of LC3-II, a widely accepted marker for autophagy. RESULTS As shown in Fig. 1, addition of geranylgeraniol in culture medium along with atorvastatin completely reversed atorvastatin-induced LC3-II expression in PC3 cells (lane 3), while geranylgeraniol alone did not have any effect on LC3-II expression (lane 7). Addition of other metabolites, such as farnesol, ubiquinone (Co-enzyme Q10), and squalene (precursor for synthesis of cholesterol) along with atorvastatin in culture medium did not affect atorvastatin-induced expression of LC3-II in PC3 cells (lanes 4-6). Furthermore, addition of geranylgeraniol, along with atorvastatin into culture medium reversed atorvastatin-caused PC3 cell death, suggesting a connection of atorvastatin-induced autophagy to rapid cell death. CONCLUSIONS Atorvastatin mediated inhibition of biosynthesis of geranylgeranyl, not farnesyl, ubiquinone or cholesterol, is the cause for the effects of atorvastatin on autophagy and autophagy-associated cell death in PC3 cells. Danville, PA© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e42 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ankur Parikh More articles by this author Chandra Childress More articles by this author Qiong Lin More articles by this author Daniel Rukstalis More articles by this author Wannian Yang More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...