title: Mitochondrial NADP(+)-dependent isocitrate dehydrogenase knockdown inhibits tumorigenicity of melanoma cells.
abstract: The potent cytotoxicity of reactive oxygen species (ROS) can cause various diseases but may also serve as a powerful weapon capable of destroying cancer cells. Although the balance between generation and elimination of ROS is maintained by the proper function of antioxidative systems, the severe disturbance of cellular redox status may cause various damages, leading to cell death. Mitochondrial NADP(+)-dependent isocitrate dehydrogenase (IDH2), an NADPH-generating enzyme, is one of the major antioxidant and redox regulators in mitochondria. To assess the effect of IDH2 knockdown in the malignancy process, we generated B16F10 melanoma cells stably transfected either with the cDNA for mouse IDH2 cloned in antisense orientation or with a control vector. Mice injected with B16F10 cells harboring IDH2 downregulation showed a dramatic reduction in tumor progression in comparison to mice administered control cells. This effect might be secondary to a shift from a reducing to an oxidative state in tumor cells. The tumor tissue of mice administered B16F10 cells transfected with the IDH2 cDNA exhibited induction of apoptosis and downregulation of angiogenesis markers. These observations demonstrate that reduction of IDH2 levels in malignant cells has anti-tumorigenic effects and suggest that IDH2 is a potential target for cancer therapy.
authors.affiliation: School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences, Kyungpook National University, Taegu 702-701, Republic of Korea.
authors.forename: Sung Hwan
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Mitochondria Hub Regulation Center, Dong-A University College of Medicine, Busan, Republic of Korea.
authors.forename: Young Hyun
authors.initials: YH
authors.lastname: Yoo
authors.affiliation: Department of Food and Biotechnology, Korea University, Sejong, Republic of Korea.
authors.forename: Jin Hyup
authors.initials: JH
authors.lastname: Lee
authors.affiliation: School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences, Kyungpook National University, Taegu 702-701, Republic of Korea. Electronic address: parkjw@knu.ac.kr.
authors.forename: Jeen-Woo
authors.initials: JW
authors.lastname: Park
mesh_terms: D000818:Animals; D017209:Apoptosis; D016373:DNA, Antisense / Q000235:genetics; D018450:Disease Progression; D055785:Gene Knockdown Techniques; D007521:Isocitrate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008546:Melanoma, Experimental / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014162:Transfection
chemical_list: D016373:DNA, Antisense; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D017382:Reactive Oxygen Species; D007521:Isocitrate Dehydrogenase; C039355:isocitrate dehydrogenase (NADP+)
keywords: Angiogenesis; Antioxidant enzyme; Melanoma; Redox status; Tumorigenesis