title: Role of reactive oxygen species-mediated mitochondrial dysregulation in 3-bromopyruvate induced cell death in hepatoma cells : ROS-mediated cell death by 3-BrPA.
abstract: Hexokinase type II (HK II) is the key enzyme for maintaining increased glycolysis in cancer cells where it is overexpressed. 3-bromopyruvate (3-BrPA), an inhibitor of HK II, induces cell death in cancer cells. To elucidate the molecular mechanism of 3-BrPA-induced cell death, we used the hepatoma cell lines SNU449 (low expression of HKII) and Hep3B (high expression of HKII). 3-BrPA induced ATP depletion-dependent necrosis and apoptosis in both cell lines. 3-BrPA increased intracellular reactive oxygen species (ROS) leading to mitochondrial dysregulation. NAC (N-acetyl-L: -cysteine), an antioxidant, blocked 3-BrPA-induced ROS production, loss of mitochondrial membrane potential and cell death. 3-BrPA-mediated oxidative stress not only activated poly-ADP-ribose (PAR) but also translocated AIF from the mitochondria to the nucleus. Taken together, 3-BrPA induced ATP depletion-dependent necrosis and apoptosis and mitochondrial dysregulation due to ROS production are involved in 3-BrPA-induced cell death in hepatoma cells.
authors.affiliation: Department of Microbiology and Brain Korea 21 Project for Medical Sciences, Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, 134, Shinchon-dong, Seodaemoon-gu, 120-752, Seoul, South Korea.
authors.forename: Ji Su
authors.initials: JS
authors.lastname: Kim
authors.forename: Keun Jae
authors.initials: KJ
authors.lastname: Ahn
authors.forename: Jeong-Ah
authors.initials: JA
authors.lastname: Kim
authors.forename: Hye Mi
authors.initials: HM
authors.lastname: Kim
authors.forename: Jong Doo
authors.initials: JD
authors.lastname: Lee
authors.forename: Jae Myun
authors.initials: JM
authors.lastname: Lee
authors.forename: Se Jong
authors.initials: SJ
authors.lastname: Kim
authors.forename: Jeon Han
authors.initials: JH
authors.lastname: Park
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006593:Hexokinase / Q000037:antagonists & inhibitors*; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology*; D011773:Pyruvates / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D011773:Pyruvates; D017382:Reactive Oxygen Species; C017092:bromopyruvate; D006593:Hexokinase