title: Switch of glycolysis to gluconeogenesis by dexamethasone for treatment of hepatocarcinoma.
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.
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China [2].
authors.forename: Ruihua
authors.initials: R
authors.lastname: Ma
authors.forename: Wanguang
authors.initials: W
authors.lastname: Zhang
authors.forename: Ke
authors.initials: K
authors.lastname: Tang
authors.forename: Huafeng
authors.initials: H
authors.lastname: Zhang
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Dapeng
authors.initials: D
authors.lastname: Li
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.forename: Pingwei
authors.initials: P
authors.lastname: Xu
authors.forename: Shunqun
authors.initials: S
authors.lastname: Luo
authors.forename: Wenqian
authors.initials: W
authors.lastname: Cai
authors.forename: Tiantian
authors.initials: T
authors.lastname: Ji
authors.forename: Foad
authors.initials: F
authors.lastname: Katirai
authors.forename: Duyun
authors.initials: D
authors.lastname: Ye
authors.forename: Bo
authors.initials: B
authors.lastname: Huang
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics / Q000378:metabolism; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D003907:Dexamethasone / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005938:Glucocorticoids / Q000494:pharmacology*; D005943:Gluconeogenesis / Q000187:drug effects*; D006019:Glycolysis / Q000187:drug effects*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009374:Neoplasms, Experimental; D061251:Primary Cell Culture; D011379:Prognosis; D015398:Signal Transduction; D016019:Survival Analysis
chemical_list: D005938:Glucocorticoids; D003907:Dexamethasone; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2