title: Two p53-related metabolic regulators, TIGAR and SCO2, contribute to oroxylin A-mediated glucose metabolism in human hepatoma HepG2 cells.
abstract: Metabolic alteration in cancer cells is one of the most conspicuous characteristics that distinguish cancer cells from normal cells. Many studies suggest that several underlying mechanisms lead to the Warburg effect (increased aerobic glycolysis) during cancer development. Here, we explored how oroxylin A affected the glycolytic metabolism in cancer cells and the underlying mechanism involved in this process. Our data revealed that both oroxylin A and adriamycin could inhibit lactate generation and glucose uptake in HepG2 cells at mild concentrations, without causing robust cell apoptosis. Oroxylin A has exerted little influence on the oxygen consumption, whereas adriamycin decreased oxygen consumption in a concentration-dependent manner. Moreover, oroxylin A could increase protein and mRNA expression of TP53-induced glycolysis and apoptosis regulator (TIGAR) and synthesis of cytochrome c oxidase 2 (SCO2), which are the key metabolic modulators regulated by p53. Meanwhile adriamycin could increase protein and mRNA expression of TIGAR and SCO2, but decrease that of phosphoglycerate mutase (PGM). Oroxylin A and adriamycin also modulated the stability and activity of p53 through inducing phosphorylation of p53 at Ser15 and suppressing the expression of MDM2. Furthermore, p53 siRNA and p53 inhibitor assay in wild-type p53 HepG2 cells both revealed the key role of p53 in oroxylin A and adriamycin-mediated glycolytic metabolism regulation. Transfecting wt p53 plasmid to p53-deficient H1299 cells could inverse some of the metabolic characteristics regulated by oroxylin A. This study revealed a new aspect of glucose metabolism regulation of oroxylin A, which may contribute to its new anticancer mechanism.
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China.
authors.forename: Qinsheng
authors.initials: Q
authors.lastname: Dai
authors.forename: Yuehan
authors.initials: Y
authors.lastname: Yin
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Libin
authors.initials: L
authors.lastname: Wei
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Zhou
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Li
authors.forename: Qidong
authors.initials: Q
authors.lastname: You
authors.forename: Na
authors.initials: N
authors.lastname: Lu
authors.forename: Qinglong
authors.initials: Q
authors.lastname: Guo
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001692:Biological Transport; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D002352:Carrier Proteins / Q000096:biosynthesis / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004317:Doxorubicin / Q000378:metabolism; D004734:Energy Metabolism; D005419:Flavonoids / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis / Q000502:physiology; D056945:Hep G2 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D019344:Lactic Acid / Q000096:biosynthesis; D008113:Liver Neoplasms; D024101:Mitochondrial Proteins / Q000096:biosynthesis / Q000378:metabolism*; D018832:Molecular Chaperones; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption; D010736:Phosphoglycerate Mutase / Q000096:biosynthesis / Q000235:genetics; D010744:Phosphoric Monoester Hydrolases; D010766:Phosphorylation; D051736:Proto-Oncogene Proteins c-mdm2 / Q000096:biosynthesis; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D005419:Flavonoids; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C400285:SCO2 protein, human; D016159:Tumor Suppressor Protein p53; D019344:Lactic Acid; C080669:5,7-dihydroxy-6-methoxy-2-phenylchromen-4-one; D004317:Doxorubicin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D010744:Phosphoric Monoester Hydrolases; C512708:TIGAR protein, human; D010736:Phosphoglycerate Mutase; D005947:Glucose