Open AccessIsocitrate dehydrogenase 1 is downregulated during early skin tumorigenesis which can be inhibited by overexpression of manganese superoxide dismutase
Author(s) -
Robbins Delira,
Wittwer Jennifer A.,
Codarin Sarah,
Circu Magdalena L.,
Aw Tak Yee,
Huang TingTing,
Van Remmen Holly,
Richardson Arlan,
Wang David B.,
Witt Stephan N.,
Klein Ronald L.,
Zhao Yunfeng
Publication year - 2012
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2012.02317.x
Subject(s) - carcinogenesis , isocitrate dehydrogenase , superoxide dismutase , tumor promotion , cancer research , biology , malignant transformation , microbiology and biotechnology , chemistry , oxidative stress , cancer , biochemistry , enzyme , genetics
Isocitrate dehydrogenase 1 ( IDH 1), a cytosolic enzyme that converts isocitrate to alpha‐ketoglutarate, has been shown to be dysregulated during tumorigenesis. However, at what stage of cancer development IDH 1 is dysregulated and how IDH 1 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 IDH 1 in early skin tumorigenesis. Our studies demonstrate that both the tumor promoter TPA and UVC irradiation decreased expression and activity levels of IDH 1, not IDH 2, in the tumor promotable JB 6 P + cell model. Skin epidermal tissues treated with dimethylbenz[α]anthracene/ TPA also showed decreases in IDH 1 expression and activity. In non‐promotable JB 6 P ‐cells, IDH 1 was upregulated upon TPA treatment, whereas IDH 2 was maintained at similar levels with TPA treatment. Interestingly, IDH 1 knockdown enhanced, whereas IDH 1 overexpression suppressed, TPA ‐induced cell transformation. Finally, manganese superoxide dismutase overexpression suppressed tumor promoter induced decreases in IDH 1 expression and mitochondrial respiration, while intracellular alpha‐ketoglutarate levels were unchanged. These results suggest that decreased IDH 1 expression in early stage skin tumorigenesis is highly correlated with tumor promotion. In addition, oxidative stress might contribute to IDH 1 inactivation, because manganese superoxide dismutase, a mitochondrial antioxidant enzyme, blocked decreases in IDH 1 expression and activity. ( Cancer Sci , doi: 10.1111/j.1349‐7006.2012.02317.x, 2012)