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; Bo Huang

doi:10.1038/ncomms3508

Switch of glycolysis to gluconeogenesis by dexamethasone for treatment of hepatocarcinoma

Nat Commun. 2013:4:2508. doi: 10.1038/ncomms3508.

Authors

Ruihua Ma¹, Wanguang Zhang, Ke Tang, Huafeng Zhang, Yi Zhang, Dapeng Li, Yong Li, Pingwei Xu, Shunqun Luo, Wenqian Cai, Tiantian Ji, Foad Katirai, Duyun Ye, Bo Huang

Affiliation

¹ 1] Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China [2].

PMID: 24149070
DOI: 10.1038/ncomms3508

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

11-beta-Hydroxysteroid Dehydrogenase Type 1 / genetics
11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism
11-beta-Hydroxysteroid Dehydrogenase Type 2 / genetics
11-beta-Hydroxysteroid Dehydrogenase Type 2 / metabolism
Animals
Base Sequence
Carcinoma, Hepatocellular / drug therapy
Carcinoma, Hepatocellular / genetics*
Carcinoma, Hepatocellular / mortality
Carcinoma, Hepatocellular / pathology
Dexamethasone / pharmacology*
Female
Gene Expression Regulation, Neoplastic
Glucocorticoids / pharmacology*
Gluconeogenesis / drug effects*
Glycolysis / drug effects*
Hepatocytes / drug effects
Hepatocytes / metabolism
Hepatocytes / pathology
Humans
Liver Neoplasms / drug therapy
Liver Neoplasms / genetics*
Liver Neoplasms / mortality
Liver Neoplasms / pathology
Mice
Mice, Inbred BALB C
Molecular Sequence Data
Neoplasms, Experimental
Primary Cell Culture
Prognosis
Signal Transduction
Survival Analysis

Substances

Glucocorticoids
Dexamethasone
11-beta-Hydroxysteroid Dehydrogenase Type 1
11-beta-Hydroxysteroid Dehydrogenase Type 2