Retinoic acid‐related orphan receptor alpha reprograms glucose metabolism in glutamine‐deficient hepatoma cells

谷氨酰胺 丙酮酸脱氢酶激酶 烟酰胺腺嘌呤二核苷酸 生物化学 核受体 生物 糖酵解 NAD+激酶 烟酰胺腺嘌呤二核苷酸磷酸 维甲酸 丙酮酸脱氢酶复合物 癌症研究 化学 分子生物学 转录因子 新陈代谢 基因 氨基酸 氧化酶试验
作者
Jun‐Kyu Byun,Yeon‐Kyung Choi,Yu Na Kang,Byoung Kuk Jang,Koo Jeong Kang,Yong Hyun Jeon,Ho‐Won Lee,Jae‐Han Jeon,Seung‐Hoi Koo,Won‐Il Jeong,Robert A. Harris,In‐Kyu Lee,Keun‐Gyu Park
出处
期刊:Hepatology [Wiley]
卷期号:61 (3): 953-964 被引量:52
标识
DOI:10.1002/hep.27577
摘要

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. (H epatology 2015;61:953–964)
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