1330 CONSUMPTION OF OXYGEN: A MITOCHONDRIAL-GENERATED PROGRESSION SIGNAL OF ADVANCED CANCER

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research (VI)1 Apr 20131330 CONSUMPTION OF OXYGEN: A MITOCHONDRIAL-GENERATED PROGRESSION SIGNAL OF ADVANCED CANCER Ara Kim, Cody Cook, Akinobu Gotoh, Rodney Davis, and Masahiro Higuchi Ara KimAra Kim Little Rock, AR More articles by this author , Cody CookCody Cook Little Rock, AR More articles by this author , Akinobu GotohAkinobu Gotoh Nishinomiya, Japan More articles by this author , Rodney DavisRodney Davis Little Rock, AR More articles by this author , and Masahiro HiguchiMasahiro Higuchi Little Rock, AR More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.2684AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The majority of mortality from prostate cancer occurs when the disease progresses to a highly malignant phenotype. Changes in the mitochondrial genome such as mutation, deletion and depletion are common in cancer and can determine advanced stages of cancer phenotypes; however, detailed mechanisms have not been elucidated. METHODS We observed that loss of the mitochondrial genome reversibly induced overexpression and activation of proto-oncogenic Ras, especially KRas-4A, which is responsible for the activation of AKT and ERK that leads to advanced phenotypes of prostate and breast cancer. Maturation of Ras, possibly by a prenylation mechanism, was required for Ras activation and was induced by the overexpression of 3- hydroxy-3-methyl-glutaryl-CoA reductase (HMGR), the rate-limiting enzyme of the mevalonate pathway. Hypoxia is known to cause accumulation of intermediate sterols that induce proteasomal degradation of HMGR. RESULTS Well-differentiated and less aggressive prostate and breast cancer cells, which have a relatively high mitochondrial DNA (mtDNA) content compared to more aggressive phenotypes, consumed a large amount of oxygen and generated intracellular hypoxia. Loss of mitochondrial genome content reduced oxygen consumption and generated an increase in oxygen concentration (hypoxic-to-normoxic shift) in the cells. Inhibition of oxygen consumption, by the reduction of mitochondrial genome content, induced overexpression of HMGR through the hypoxic-to-normoxic shift. Subsequently, the endogenous induction of the mevalonate pathway increased farnesylation (membrane localization) of Ras, which lead to the activation of Ras that mediates the advanced phenotype. Reconstitution of the mitochondrial genome or the external hypoxic condition, as a means to reverse the hypoxic-to-normoxic shift, diminished the endogenous induction of the mevalonate pathway, and inhibited the farnesylation and activation of proto-oncogenic Ras. Moreover, reduction of mitochondrial genome content was associated with the aggressive phenotype of prostate cancer in an in vitro cell line model and prostate cancer from tissue specimens of patients. CONCLUSIONS Our results elucidated a coherent mechanism that directly links changes in the mitochondrial genome with the advanced progression of the disease. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e543 Peer Review Report Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ara Kim Little Rock, AR More articles by this author Cody Cook Little Rock, AR More articles by this author Akinobu Gotoh Nishinomiya, Japan More articles by this author Rodney Davis Little Rock, AR More articles by this author Masahiro Higuchi Little Rock, AR More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...