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

Robbins, Delira; Wittwer, Jennifer; Codarin, Sarah; Circu, Magdalena L.; Aw, Tak Yee; Huang, Ting; Remmen, Holly Van; Richardson, Arlan; Wang, David B.; Witt, Stephan N.; Klein, Ronald L.; Zhao, Yunfeng

doi:10.1111/j.1349-7006.2012.02317.x

Cited by 14 publications

(24 citation statements)

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“…Our previous study showed that tumor promoter decreased the expression and activity levels of IDH1, but not IDH2, in the tumor promotable JB6 P+ cell model. (16) In the present study, our data show that WA suppresses the decreases in IDH1 protein expression and activity during the early stage of skin carcinogenesis. Importantly, we found that WA directly increased IDH1 activity, suggesting IDH1 might be a potential target of WA.…”

Section: Discussionmentioning

confidence: 55%

“…In addition, knockdown of IDH1 enhances whereas overexpression of IDH1 suppresses skin cell transformation, suggesting a tumor suppressive role for IDH1 in the early stage of skin carcinogenesis. (16) In addition, the expression and activity levels of IDH2 are not altered by tumor promoter treatment. In the present study, we found that WA promotes the conversion of isocitrate to a-KG.…”

Section: Discussionmentioning

confidence: 99%

“…(11,12) However, the role of IDH1 in early cancer development is not completely understood. Our previous study (16) revealed that decreased IDH1 expression enhances whereas increased IDH1 expression suppresses skin cell transformation, suggesting IDH1 activity is important for suppressing tumor promotion. To study whether WA can affect cellular metabolism and IDH1 activity in the early stage of carcinogenesis, we treated mouse skin with DMBA and TPA and isolated skin cells.…”

Section: Resultsmentioning

confidence: 99%

“…Mutant IDH1 gains a new function, which produces 2-hydroxyglutatarate. (14) Based on our previous studies, (16) both UV irradiation (in vitro) and tumor promoter TPA (in vitro and in vivo) cause downregulation of IDH1 expression and activity in skin epidermal cells. In addition, knockdown of IDH1 enhances whereas overexpression of IDH1 suppresses skin cell transformation, suggesting a tumor suppressive role for IDH1 in the early stage of skin carcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…(16) Whether IDH1 and mitochondrial function might be a potent target of WA, which leads to suppression of skin cell transformation, will be investigated using JB6 cells and skin epidermal tissues. These models are well established for screening cancer prevention agents and for mechanistic studies, and therefore suitable for our purpose.…”

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confidence: 99%

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Withaferin A suppresses tumor promoter 12‐O‐tetradecanoylphorbol 13‐acetate‐induced decreases in isocitrate dehydrogenase 1 activity and mitochondrial function in skin epidermal JB6 cells

Zhao

2012

Cancer Science

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Withaferin A (WA) is a bioactive compound derived from Withania somnifera. The antitumor activity of WA has been well studied in human cancer models; however, its chemopreventive potential is unclear. In the present study, we used the skin epidermal JB6 P+ cells, a well-established model for tumor promotion, and demonstrated that WA suppressed the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced cell transformation and cell proliferation. Interestingly, TPA inactivated isocitrate dehydrogenase 1 (IDH1), which was reversed by WA. Similar results were also observed in mouse skin tissue. Therefore, we focused on metabolism as the potential mechanism of action. We found that mitochondrial functions were downregulated by TPA treatment, as indicated by reduced mitochondrial membrane potential, complex I activity and mitochondrial respiration. However, all of these downregulations were inhibited by WA. In addition, we examined the levels of a-ketoglutarate, a product of IDH1, and WA blocked its reduction upon TPA treatment. Finally, we detected the lactate level as a glycolysis marker, and WA suppressed its elevation caused by tumor promoter treatment. Altogether, these results suggest that WA might exert its chemopreventive activity via inhibiting not only oncogenic activation, but also IDH1 inactivation and mitochondrial dysfunction in early tumorigenesis. (Cancer Sci 2013; 104: 143-148) W ithaferin A (WA; Supporting Information Fig. S1) belongs to a group of biologically active constituents known as withanolides. The antitumor activity of WA has been reported, which shows that WA suppresses human breast cancer, (1,2) prostate cancer, (3) colon cancer, (4) pancreatic cancer,glioma, (6) renal cancer (7) and leukemia. (8) Moreover, a clinical trial of WA has been launched for treatment of metastatic melanoma.(9) Not surprising, Withania somnifera is within the high-priority topics from the National Center for Complementary and Alternative Medicine. However, the chemopreventive potential of WA has not been well studied. Therefore, testing the mechanism of action of WA in chemoprevention using well-established skin cell transformation and skin carcinogenesis models is important.Carcinogenesis is often associated with a metabolic shift. Cancer cells predominantly produce energy by a high rate of glycolysis followed by lactic acid fermentation even in the presence of oxygen, known as the "Warburg effect".(10) Although glycolysis is inefficient at producing ATP compared with oxidative phosphorylation (OXPHOS), the metabolic intermediates produced during glycolysis might provide a growth advantage for cancer cells. Associated with this metabolic switch is dysregulation of important metabolic enzymes. Isocitrate dehydrogenase (IDH), as a metabolic enzyme converting isocitrate to a-ketoglutarate, consists of three isoforms. Mutations in IDH1 and IDH2 have been found in glioma (11) and leukemia, (12) and IDH2 mutation is much less common than IDH1 mutation. Mutations in IDH1 impair its enzymatic activity, l...

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Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Withaferin A suppresses tumor promoter 12‐O‐tetradecanoylphorbol 13‐acetate‐induced decreases in isocitrate dehydrogenase 1 activity and mitochondrial function in skin epidermal JB6 cells

Zhao

2012

Cancer Science

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Metformin prevents DMH‐induced colorectal cancer in diabetic rats by reversing the warburg effect

Jia

Liu

et al. 2015

Cancer Medicine

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Epidemiologic studies have shown that the treatment of diabetics with metformin reduced the risk of cancer-related mortality. Here, we investigated the chemopreventive effects of metformin on dimethylhydrazine (DMH)-induced colorectal carcinogenesis in diabetic SD rats following metformin treatment and the effect on Warburg effect involved in this process. Diabetic rat models were induced with high-fat feeding in combination with a low dose of Streptozotocin (STZ) and then induce colorectal cancer with a low dose of DMH. The formation of colorectal Aberrant crypt foci (ACF) and the incidence, number and size of the tumor were measured. The proliferation indices of colonic tissues were determined through Proliferating cell nuclear antigen (PCNA) immunostaining. Then detect the expression of PK and IDH in colonic tissues using immunohistochemistry and Western blot. The enzyme activities of HK and PDH in colonic tissues were measured. The growth and expression of PK and IDH and activity of HK and PDH in cell lines LoVo and HT-29 were measured after metformin treatment. The results showed that metformin treatment significantly inhibited the formation of ACF and tumors. The proliferation index of colonic tissues was significantly decreased following metformin treatment. In addition, metformin inhibited cell growth and decreased the imbalance in the expression of the enzymes involved in glycolysis and the TCA cycle. These findings suggested that metformin might produce a synergistic colon cancer-preventative effect in diabetic patients through the regulation of the enzymes expression involved in glucose metabolism.

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Integrated Proteogenomic Characterization across Major Histological Types of Pediatric Brain Cancer

Petralia

Tignor

Reva

et al. 2020

Cell

226

186

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

Cited by 14 publications

References 14 publications

Withaferin A suppresses tumor promoter 12‐O‐tetradecanoylphorbol 13‐acetate‐induced decreases in isocitrate dehydrogenase 1 activity and mitochondrial function in skin epidermal JB6 cells

Withaferin A suppresses tumor promoter 12‐O‐tetradecanoylphorbol 13‐acetate‐induced decreases in isocitrate dehydrogenase 1 activity and mitochondrial function in skin epidermal JB6 cells

Metformin prevents DMH‐induced colorectal cancer in diabetic rats by reversing the warburg effect

Integrated Proteogenomic Characterization across Major Histological Types of Pediatric Brain Cancer

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