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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Melatonin inhibits glycolysis in hepatocellular carcinoma cells by downregulating mitochondrial respiration and mTORC1 activity

  • Lee, Seunghyeong (Department of Biomedical Science, Graduate School, Kyungpook National University) ;
  • Byun, Jun-Kyu (Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University) ;
  • Kim, Na-Young (Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital) ;
  • Jin, Jonghwa (Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital) ;
  • Woo, Hyein (Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital) ;
  • Choi, Yeon-Kyung (Research Institute of Aging and Metabolism, Kyungpook National University) ;
  • Park, Keun-Gyu (Department of Biomedical Science, Graduate School, Kyungpook National University)
  • Received : 2021.12.09
  • Accepted : 2022.03.23
  • Published : 2022.09.30
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Abstract

Various mechanisms have been suggested to explain the chemopreventive and tumor-inhibitory effects of melatonin. Despite the growing evidence supporting melatonin-induced mitochondrial dysfunction, it remains largely unknown how this phenomenon modulates metabolic reprogramming in cancer cells. The aim of our study was to identify the mechanism underlying the anti-proliferative and apoptotic effects of melatonin, which is known to inhibit glycolysis. We analyzed the time-dependent effects of melatonin on mitochondrial respiration and glycolysis in liver cancer cells. The results showed that from a cell bioenergetic point of view, melatonin caused an acute reduction in mitochondrial respiration, however, increased reactive oxygen species production, thereby inhibiting mTORC1 activity from an early stage post-treatment without affecting glycolysis. Nevertheless, administration of melatonin for a longer time reduced expression of c-Myc protein, thereby suppressing glycolysis via downregulation of HK2 and LDHA. The data presented herein suggest that melatonin suppresses mitochondrial respiration and glycolysis simultaneously in HCC cells, leading to anti-cancer effects. Thus, melatonin can be used as an adjuvant agent for therapy of liver cancer.

Keywords

Acknowledgement

This work was supported by National Research Foundation of Korea (NRF) grants NRF-2017M3A9G7073086, NRF-2021R1A2C3005603, NRF-2020R1A5A2017323, NRF-2022R1A2C1008591, and NRF-2021R1C1C2003405, funded by the Ministry of Science and ICT.

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