Switch of glycolysis to gluconeogenesis by dexamethasone for treatment of hepatocarcinoma

Ruihua Ma, Wanguang Zhang, Ke Tang, Huafeng Zhang, Yi Zhang, Dapeng Li, Yong Li, Pingwei Xu, Shunqun Luo, Wenqian Cai, Tiantian Ji, Foad Katirai, Duyun Ye and Bo Huang ()
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Ruihua Ma: Tongji Medical College, Huazhong University of Science and Technology
Wanguang Zhang: Tongji Medical College, Huazhong University of Science and Technology
Ke Tang: Tongji Medical College, Huazhong University of Science and Technology
Huafeng Zhang: Tongji Medical College, Huazhong University of Science and Technology
Yi Zhang: Tongji Medical College, Huazhong University of Science and Technology
Dapeng Li: Tongji Medical College, Huazhong University of Science and Technology
Yong Li: Tongji Medical College, Huazhong University of Science and Technology
Pingwei Xu: Tongji Medical College, Huazhong University of Science and Technology
Shunqun Luo: Tongji Medical College, Huazhong University of Science and Technology
Wenqian Cai: Tongji Medical College, Huazhong University of Science and Technology
Tiantian Ji: Tongji Medical College, Huazhong University of Science and Technology
Foad Katirai: Tongji Medical College, Huazhong University of Science and Technology
Duyun Ye: Tongji Medical College, Huazhong University of Science and Technology
Bo Huang: Tongji Medical College, Huazhong University of Science and Technology

Nature Communications, 2013, vol. 4, issue 1, 1-12

Abstract: Abstract Gluconeogenesis is a fundamental feature of hepatocytes. Whether this gluconeogenic activity is also present in malignant hepatocytes remains unexplored. A better understanding of this biological process may lead to novel therapeutic strategies. Here we show that gluconeogenesis is not present in mouse or human malignant hepatocytes. We find that two critical enzymes 11β-HSD1 and 11β-HSD2 that regulate glucocorticoid activities are expressed inversely in malignant hepatocytes, resulting in the inactivation of endogenous glucocorticoids and the loss of gluconeogenesis. In patients’ hepatocarcinoma, the expression of 11β-HSD1 and 11β-HSD2 is closely linked to prognosis and survival. Dexamethasone, an active form of synthesized glucocorticoids, is capable of restoring gluconeogenesis in malignant cells by bypassing the abnormal regulation of 11β-HSD enzymes, leading to therapeutic efficacy against hepatocarcinoma. These findings clarify the molecular basis of malignant hepatocyte loss of gluconeogenesis and suggest new therapeutic strategies.

Date: 2013
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DOI: 10.1038/ncomms3508

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