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Retinoic Acid-Related Orphan Receptor Alpha Reprograms Glucose Metabolism in Glutamine-Deficient Hepatoma Cells

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Author(s)
Jun-Kyu ByunYeon-Kyung ChoiYu Na KangByoung Kuk JangKoo Jeong KangYong Hyun JeonHo-Won LeeJae-Han JeonSeung-Hoi KooWon-Il JeongRobert A. HarrisIn-Kyu LeeKeun-Gyu Park
Keimyung Author(s)
Kang, Yu NaJang, Byoung KukKang, Koo Jeong
Department
Dept. of Pathology (병리학)
Dept. of Internal Medicine (내과학)
Dept. of Surgery (외과학)
Journal Title
Hepatology
Issued Date
2015
Volume
61
Issue
3
Abstract
The metabolism of glutamine and glucose is recognized as a promising therapeutic target for the treatment of cancer; however, targeted molecules that mediate glutamine and glucose metabolism in cancer cells have not been addressed. Here, we show that restricting the supply of glutamine in hepatoma cells, including HepG2 and Hep3B cells, markedly increased the expression of retinoic acid-related orphan receptor alpha (RORα). Up-regulation of RORα in glutamine-deficient hepatoma cells resulted from an increase in the level of cellular reactive oxygen species and in the nicotinamide adenine dinucleotide phosphate/nicotinamide adenine dinucleotide phosphate reduced (NADP+/NADPH) ratio, which was consistent with a reduction in the glutathione/glutathione disulfide (GSH/GSSG) ratio. Adenovirus (Ad)-mediated overexpression of RORα (Ad-RORα) or treatment with the RORα activator, SR1078, reduced aerobic glycolysis and down-regulated biosynthetic pathways in hepatoma cells. Ad-RORα and SR1078 reduced the expression of pyruvate dehydrogenase kinase 2 (PDK2) and inhibited the phosphorylation of pyruvate dehydrogenase and subsequently shifted pyruvate to complete oxidation. The RORα-mediated decrease in PDK2 levels was caused by up-regulation of p21, rather than p53. Furthermore, RORα inhibited hepatoma growth both in vitro and in a xenograft model in vivo. We also found that suppression of PDK2 inhibited hepatoma growth in a xenograft model. These findings mimic the altered glucose utilization and hepatoma growth caused by glutamine deprivation. Finally, tumor tissue from 187 hepatocellular carcinoma patients expressed lower levels of RORα than adjacent nontumor tissue, supporting a potential beneficial effect of RORα activation in the treatment of liver cancer. Conclusion: RORα mediates reprogramming of glucose metabolism in hepatoma cells in response to glutamine deficiency. The relationships established here between glutamine metabolism, RORα expression and signaling, and aerobic glycolysis have implications for therapeutic targeting of liver cancer metabolism. (Hepatology 2015;61:953–964)
Keimyung Author(s)(Kor)
강유나
장병국
강구정
Publisher
School of Medicine
Citation
Jun-Kyu Byun et al. (2015). Retinoic Acid-Related Orphan Receptor
Alpha Reprograms Glucose Metabolism in
Glutamine-Deficient Hepatoma Cells. Hepatology, 61(3), 953–964. doi: 10.1002/hep.27577
Type
Article
ISSN
0270-9139
DOI
10.1002/hep.27577
URI
https://kumel.medlib.dsmc.or.kr/handle/2015.oak/35828
Appears in Collections:
1. School of Medicine (의과대학) > Dept. of Internal Medicine (내과학)
1. School of Medicine (의과대학) > Dept. of Pathology (병리학)
1. School of Medicine (의과대학) > Dept. of Surgery (외과학)
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