Role of reactive oxygen species-mediated mitochondrial dysregulation in 3-bromopyruvate induced cell death in hepatoma cells : ROS-mediated cell death by 3-BrPA.
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.
Kim
Ji Su
JS
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.
Ahn
Keun Jae
KJ
Kim
Jeong-Ah
JA
Kim
Hye Mi
HM
Lee
Jong Doo
JD
Lee
Jae Myun
JM
Kim
Se Jong
SJ
Park
Jeon Han
JH
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*
D011773:Pyruvates; D017382:Reactive Oxygen Species; C017092:bromopyruvate; D006593:Hexokinase