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

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

Research output: Contribution to journalArticle

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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<sup>+</sup>/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.

Original languageEnglish
Pages (from-to)953-964
Number of pages12
JournalHepatology
Volume61
Issue number3
DOIs
Publication statusPublished - 2015 Mar 1

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Tretinoin
Glutamine
Hepatocellular Carcinoma
Glucose
NADP
Glutathione Disulfide
Glycolysis
Liver Neoplasms
Pyruvic Acid
Heterografts
Adenoviridae
Up-Regulation
Growth
Therapeutics
Neoplasms
Biosynthetic Pathways
Hep G2 Cells
Glutathione
Reactive Oxygen Species
Oxidoreductases

ASJC Scopus subject areas

  • Hepatology
  • Medicine(all)

Cite this

Byun, J. K., Choi, Y. K., Kang, Y. N., Jang, B. K., Kang, K. J., Jeon, Y. H., ... Park, K. G. (2015). Retinoic acid-related orphan receptor alpha reprograms glucose metabolism in glutamine-deficient hepatoma cells. Hepatology, 61(3), 953-964. https://doi.org/10.1002/hep.27577

Retinoic acid-related orphan receptor alpha reprograms glucose metabolism in glutamine-deficient hepatoma cells. / Byun, Jun Kyu; Choi, Yeon Kyung; Kang, Yu Na; Jang, Byoung Kuk; Kang, Koo Jeong; Jeon, Yong Hyun; Lee, Ho Won; Jeon, Jae Han; Koo, Seung-Hoi; Jeong, Won Il; Harris, Robert A.; Lee, In Kyu; Park, Keun Gyu.

In: Hepatology, Vol. 61, No. 3, 01.03.2015, p. 953-964.

Research output: Contribution to journalArticle

Byun, JK, Choi, YK, Kang, YN, Jang, BK, Kang, KJ, Jeon, YH, Lee, HW, Jeon, JH, Koo, S-H, Jeong, WI, Harris, RA, Lee, IK & Park, KG 2015, 'Retinoic acid-related orphan receptor alpha reprograms glucose metabolism in glutamine-deficient hepatoma cells', Hepatology, vol. 61, no. 3, pp. 953-964. https://doi.org/10.1002/hep.27577
Byun, Jun Kyu ; Choi, Yeon Kyung ; Kang, Yu Na ; Jang, Byoung Kuk ; Kang, Koo Jeong ; Jeon, Yong Hyun ; Lee, Ho Won ; Jeon, Jae Han ; Koo, Seung-Hoi ; Jeong, Won Il ; Harris, Robert A. ; Lee, In Kyu ; Park, Keun Gyu. / Retinoic acid-related orphan receptor alpha reprograms glucose metabolism in glutamine-deficient hepatoma cells. In: Hepatology. 2015 ; Vol. 61, No. 3. pp. 953-964.
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