title: NDRG2 overexpression suppresses hepatoma cells survival during metabolic stress through disturbing the activation of fatty acid oxidation.
abstract: Because of the high nutrient consumption and inadequate vascularization, solid tumor constantly undergoes metabolic stress during tumor development. Oncogenes and tumor suppressor genes participated in cancer cells' metabolic reprogramming. N-Myc downstream regulated gene 2 (NDRG2) is a recently identified tumor suppressor gene, but its function in cancer metabolism, particularly during metabolic stress, remains unclear. In this study, we found that NDRG2 overexpression significantly reduced hepatoma cell proliferation and enhanced cell apoptosis under glucose limitation. Moreover, NDRG2 overexpression aggravated energy imbalance and oxidative stress by decreasing the intracellular ATP and NADPH generation and increasing ROS levels. Strikingly, NDRG2 inhibited the activation of fatty acid oxidation (FAO), which preserves ATP and NADPH purveyance in the absence of glucose. Finally, mechanistic investigation showed that NDRG2 overexpression suppressed the glucose-deprivation induced AMPK/ACC pathway activation in hepatoma cells, whereas the expression of a constitutively active form of AMPK abrogated glucose-deprivation induced AMPK activation and cell apoptosis. Thus, as a negative regulator of AMPK, NDRG2 disturbs the induction of FAO genes by glucose limitation, leading to dysregulation of ATP and NADPH, and thus reduces the tolerance of hepatoma cells to glucose limitation.
authors.affiliation: The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi Province, China; Xi'an Medical University, Xi'an, Shaanxi Province, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Pan
authors.affiliation: The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi Province, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Respiration, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi Province, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Zhang
authors.affiliation: The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi Province, China.
authors.forename: Guang
authors.initials: G
authors.lastname: Yan
authors.affiliation: The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi Province, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Ru
authors.affiliation: The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi Province, China.
authors.forename: Qinhao
authors.initials: Q
authors.lastname: Wang
authors.affiliation: The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi Province, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi Province, China.
authors.forename: Xuehui
authors.initials: X
authors.lastname: Wei
authors.affiliation: The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi Province, China.
authors.forename: Xinyuan
authors.initials: X
authors.lastname: Xu
authors.affiliation: The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi Province, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Shen
authors.affiliation: The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi Province, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: The State Key Laboratory of Cancer Biology, Department of Gastroenterology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi Province, China.
authors.forename: Kaichun
authors.initials: K
authors.lastname: Wu
authors.affiliation: The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi Province, China. Electronic address: bioyao@fmmu.edu.cn.
authors.forename: Libo
authors.initials: L
authors.lastname: Yao
authors.affiliation: The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi Province, China. Electronic address: lixia@fmmu.edu.cn.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D005227:Fatty Acids / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D005227:Fatty Acids; C466228:NDRG2 protein, human; D025521:Tumor Suppressor Proteins; D055372:AMP-Activated Protein Kinases; C000588423:ACACA protein, human; D000103:Acetyl-CoA Carboxylase; D005947:Glucose
keywords: Cell survival; Fatty acid oxidation; Hepatocellular carcinoma; Metabolic stress; NDRG2