title: Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses.
abstract: Control of intracellular reactive oxygen species (ROS) concentrations is critical for cancer cell survival. We show that, in human lung cancer cells, acute increases in intracellular concentrations of ROS caused inhibition of the glycolytic enzyme pyruvate kinase M2 (PKM2) through oxidation of Cys(358). This inhibition of PKM2 is required to divert glucose flux into the pentose phosphate pathway and thereby generate sufficient reducing potential for detoxification of ROS. Lung cancer cells in which endogenous PKM2 was replaced with the Cys(358) to Ser(358) oxidation-resistant mutant exhibited increased sensitivity to oxidative stress and impaired tumor formation in a xenograft model. Besides promoting metabolic changes required for proliferation, the regulatory properties of PKM2 may confer an additional advantage to cancer cells by allowing them to withstand oxidative stress.
authors: Beth Israel Deaconess Medical Center, Department of Medicine-Division of Signal Transduction, Boston, MA 02115, USA.
authors: Dimitrios
authors: D
authors: Anastasiou
authors: George
authors: G
authors: Poulogiannis
authors: John M
authors: JM
authors: Asara
authors: Matthew B
authors: MB
authors: Boxer
authors: Jian-kang
authors: JK
authors: Jiang
authors: Min
authors: M
authors: Shen
authors: Gary
authors: G
authors: Bellinger
authors: Atsuo T
authors: AT
authors: Sasaki
authors: Jason W
authors: JW
authors: Locasale
authors: Douglas S
authors: DS
authors: Auld
authors: Craig J
authors: CJ
authors: Thomas
authors: Matthew G
authors: MG
authors: Vander Heiden
authors: Lewis C
authors: LC
authors: Cantley
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D019943:Amino Acid Substitution; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D003545:Cysteine / Q000737:chemistry; D003958:Diamide / Q000494:pharmacology; D020536:Enzyme Activators / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D050505:Mutant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010427:Pentose Phosphate Pathway; D021122:Protein Subunits; D011770:Pyruvate Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014183:Transplantation, Heterologous
chemical_list: D000975:Antioxidants; D020536:Enzyme Activators; D050505:Mutant Proteins; D021122:Protein Subunits; D017382:Reactive Oxygen Species; D003958:Diamide; D011770:Pyruvate Kinase; D005978:Glutathione; D005947:Glucose; D003545:Cysteine; D000111:Acetylcysteine