• Open Access

Isocitrate dehydrogenase 1 is downregulated during early skin tumorigenesis which can be inhibited by overexpression of manganese superoxide dismutase

Authors

  • Delira Robbins,

    1. Department of Pharmacology, Toxicology and Neuroscience, LSU Health Sciences Center, Shreveport, Louisiana, USA
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    • These two authors contributed equally to this manuscript.

  • Jennifer A. Wittwer,

    1. Department of Pharmacology, Toxicology and Neuroscience, LSU Health Sciences Center, Shreveport, Louisiana, USA
    2. Department of Molecular Genetics, Ohio State University, Columbus, Ohio, USA
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    • These two authors contributed equally to this manuscript.

  • Sarah Codarin,

    1. Department of Pharmacology, Toxicology and Neuroscience, LSU Health Sciences Center, Shreveport, Louisiana, USA
    2. Department of Southwood High School, Shreveport, Louisiana, USA
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  • Magdalena L. Circu,

    1. Department of Molecular and Cellular Physiology, LSU Health Sciences Center, Shreveport, Louisiana, USA
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  • Tak Yee Aw,

    1. Department of Molecular and Cellular Physiology, LSU Health Sciences Center, Shreveport, Louisiana, USA
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  • Ting-Ting Huang,

    1. Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, California, USA
    2. Department of GRECC, VA Palo Alto Health Care System, Palo Alto, California, USA
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  • Holly Van Remmen,

    1. Department of Barshop Institute for Longevity and Aging Studies, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas, USA
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  • Arlan Richardson,

    1. Department of Barshop Institute for Longevity and Aging Studies, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas, USA
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  • David B. Wang,

    1. Department of Pharmacology, Toxicology and Neuroscience, LSU Health Sciences Center, Shreveport, Louisiana, USA
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  • Stephan N. Witt,

    1. Department of Biochemistry and Molecular Biology, LSU Health Sciences Center, Shreveport, Louisiana, USA
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  • Ronald L. Klein,

    1. Department of Pharmacology, Toxicology and Neuroscience, LSU Health Sciences Center, Shreveport, Louisiana, USA
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  • Yunfeng Zhao

    Corresponding author
    1. Department of Pharmacology, Toxicology and Neuroscience, LSU Health Sciences Center, Shreveport, Louisiana, USA
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Abstract

Isocitrate dehydrogenase 1 (IDH1), a cytosolic enzyme that converts isocitrate to alpha-ketoglutarate, has been shown to be dysregulated during tumorigenesis. However, at what stage of cancer development IDH1 is dysregulated and how IDH1 may affect cell transformation and tumor promotion during early stages of cancer development are unclear. We used a skin cell transformation model and mouse skin epidermal tissues to study the role of IDH1 in early skin tumorigenesis. Our studies demonstrate that both the tumor promoter TPA and UVC irradiation decreased expression and activity levels of IDH1, not IDH2, in the tumor promotable JB6 P+ cell model. Skin epidermal tissues treated with dimethylbenz[α]anthracene/TPA also showed decreases in IDH1 expression and activity. In non-promotable JB6 P-cells, IDH1 was upregulated upon TPA treatment, whereas IDH2 was maintained at similar levels with TPA treatment. Interestingly, IDH1 knockdown enhanced, whereas IDH1 overexpression suppressed, TPA-induced cell transformation. Finally, manganese superoxide dismutase overexpression suppressed tumor promoter induced decreases in IDH1 expression and mitochondrial respiration, while intracellular alpha-ketoglutarate levels were unchanged. These results suggest that decreased IDH1 expression in early stage skin tumorigenesis is highly correlated with tumor promotion. In addition, oxidative stress might contribute to IDH1 inactivation, because manganese superoxide dismutase, a mitochondrial antioxidant enzyme, blocked decreases in IDH1 expression and activity. (Cancer Sci, doi: 10.1111/j.1349-7006.2012.02317.x, 2012)

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