title: Protein kinase C-ERK1/2 signal pathway switches glucose depletion-induced necrosis to apoptosis by regulating superoxide dismutases and suppressing reactive oxygen species production in A549 lung cancer cells.
abstract: Cells typically die by either apoptosis or necrosis. However, the consequences of apoptosis and necrosis are quite different for a whole organism. In the case of apoptosis, the cell content remains packed in the apoptotic bodies that are removed by macrophages, and thereby inflammation does not occur; during necrosis, the cell membrane is ruptured, and the cytosolic constituents are released into the extracellular space provoking inflammation. Recently, inflammation and necrosis have been suggested to promote tumor growth. We investigated the molecular mechanism underlying cell death in response to glucose depletion (GD), a common characteristic of the tumor microenvironment. GD induced necrosis through production of reactive oxygen species (ROS) in A549 lung carcinoma cells. Inhibition of ROS production by N-acetyl-L-cysteine and catalase prevented necrosis and switched the cell death mode to apoptosis that depends on mitochondrial death pathway involving caspase-9 and caspase-3 activation, indicating a critical role of ROS in determination of GD-induced cell death mode. We demonstrate that protein kinase C-dependent extracellular regulated kinase 1/2 (ERK1/2) activation also switched GD-induced necrosis to apoptosis through inhibition of ROS production possibly by inducing manganese superoxide dismutase (SOD) expression and by preventing GD-induced degradation of copper zinc SOD. Thus, these results suggest that GD-induced cell death mode is determined by the protein kinase C/ERK1/2 signal pathway that regulates MnSOD and CuZnSOD and that these antioxidants may exert their known tumor suppressive activities by inducing necrosis-to-apoptosis switch.
authors.affiliation: Department of Molecular Biology, College of Natural Sciences, and Research Institute of Genetic Engineering, Pusan National University, Pusan, Korea.
authors.forename: Cho Hee
authors.initials: CH
authors.lastname: Kim
authors.forename: Song Iy
authors.initials: SI
authors.lastname: Han
authors.forename: Su Yeon
authors.initials: SY
authors.lastname: Lee
authors.forename: Hyun Suk
authors.initials: HS
authors.lastname: Youk
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Moon
authors.forename: Hong Quan
authors.initials: HQ
authors.lastname: Duong
authors.forename: Min Jung
authors.initials: MJ
authors.lastname: Park
authors.forename: Young Mi
authors.initials: YM
authors.lastname: Joo
authors.forename: Hye Gyeong
authors.initials: HG
authors.lastname: Park
authors.forename: Yung Jin
authors.initials: YJ
authors.lastname: Kim
authors.forename: Mi Ae
authors.initials: MA
authors.lastname: Yoo
authors.forename: Sung-Chul
authors.initials: SC
authors.lastname: Lim
authors.forename: Ho Sung
authors.initials: HS
authors.lastname: Kang
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002374:Catalase / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival; D004706:Endodeoxyribonucleases / Q000378:metabolism; D004789:Enzyme Activation; D004790:Enzyme Induction; D004795:Enzyme Stability; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005947:Glucose / Q000172:deficiency*; D024243:HMGB1 Protein / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008928:Mitochondria / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009336:Necrosis; D011493:Protein Kinase C / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013482:Superoxide Dismutase / Q000096:biosynthesis*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors
chemical_list: C494829:AIFM1 protein, human; D000975:Antioxidants; D051033:Apoptosis Inducing Factor; D024243:HMGB1 Protein; D017382:Reactive Oxygen Species; D002374:Catalase; D013482:Superoxide Dismutase; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D004706:Endodeoxyribonucleases; C052391:endonuclease G; D053148:Caspase 3; D053453:Caspase 9; D005947:Glucose; D013755:Tetradecanoylphorbol Acetate; D000111:Acetylcysteine