Melatonin inhibits glycolysis in hepatocellular carcinoma cells by downregulating mitochondrial respiration and mTORC1 activity
1
조회
0
다운로드
2
인용
0
참고문헌
키워드
초록
Various mechanisms have been suggested to explain the chemopreventiveand tumor-inhibitory effects of melatonin. Despite thegrowing evidence supporting melatonin-induced mitochondrialdysfunction, it remains largely unknown how this phenomenonmodulates metabolic reprogramming in cancer cells. The aim ofour study was to identify the mechanism underlying the anti-proliferativeand apoptotic effects of melatonin, which is known toinhibit glycolysis. We analyzed the time-dependent effects ofmelatonin on mitochondrial respiration and glycolysis in livercancer cells. The results showed that from a cell bioenergeticpoint of view, melatonin caused an acute reduction in mitochondrialrespiration, however, increased reactive oxygen speciesproduction, thereby inhibiting mTORC1 activity from an earlystage post-treatment without affecting glycolysis. Nevertheless,administration of melatonin for a longer time reduced expressionof c-Myc protein, thereby suppressing glycolysis via downregulationof HK2 and LDHA. The data presented herein suggest thatmelatonin suppresses mitochondrial respiration and glycolysissimultaneously in HCC cells, leading to anti-cancer effects. Thus,melatonin can be used as an adjuvant agent for therapy of livercancer.
Abstract
Various mechanisms have been suggested to explain the chemopreventiveand tumor-inhibitory effects of melatonin. Despite thegrowing evidence supporting melatonin-induced mitochondrialdysfunction, it remains largely unknown how this phenomenonmodulates metabolic reprogramming in cancer cells. The aim ofour study was to identify the mechanism underlying the anti-proliferativeand apoptotic effects of melatonin, which is known toinhibit glycolysis. We analyzed the time-dependent effects ofmelatonin on mitochondrial respiration and glycolysis in livercancer cells. The results showed that from a cell bioenergeticpoint of view, melatonin caused an acute reduction in mitochondrialrespiration, however, increased reactive oxygen speciesproduction, thereby inhibiting mTORC1 activity from an earlystage post-treatment without affecting glycolysis. Nevertheless,administration of melatonin for a longer time reduced expressionof c-Myc protein, thereby suppressing glycolysis via downregulationof HK2 and LDHA. The data presented herein suggest thatmelatonin suppresses mitochondrial respiration and glycolysissimultaneously in HCC cells, leading to anti-cancer effects. Thus,melatonin can be used as an adjuvant agent for therapy of livercancer.
참고문헌 (22)
- Cohen M, "Role of pineal gland in aetiology and treatment of breast cancer", Lancet, 2, pp.814~816 (1978)
- Jung B, "Melatonin in cancer management : progress and promise", Cancer Res, 66, pp.9789~9793 (2006)
- Mehrzadi S, "An updated review of mechanistic potentials of melatonin against cancer : pivotal roles in angiogenesis, apoptosis, autophagy, endoplasmic reticulum stress and oxidative stress", Cancer Cell Int, 21, pp.188~ (2021)
- Sarti P, "New evidence for cross talk between melatonin and mitochondria mediated by a circadian-compatible interaction with nitric oxide", Int J Mol Sci, 14, pp.11259~11276 (2013)
- Lee S, "Melatonin inhibits vascular smooth muscle cell proliferation and apoptosis through upregulation of Sestrin2", Exp Ther Med, 19, pp.3454~3460 (2020)
- Fernandez-Gil BI, "Melatonin enhances cisplatin and radiation cytotoxicity in head and neck squamous cell carcinoma by stimulating mitochondrial ros generation, apoptosis, and autophagy", Oxid Med Cell Longev, 2019, pp.7187128~ (2019)
- Luchetti F, "Melatonin signaling and cell protection function", Faseb j, 24, pp.3603~3624 (2010)
- DeBerardinis RJ, "The biology of cancer : metabolic reprogramming fuels cell growth and proliferation", Cell Metab, 7, pp.11~20 (2008)
- Yecies JL, "Transcriptional control of cellular metabolism by mTOR signaling", Cancer Res, 71, pp.2815~2820 (2011)
- Salmond RJ, "mTOR regulation of glycolytic metabolism in T cells", Front Cell Dev Biol, 6, pp.122~ (2018)
- Hevia D, "Melatonin decreases glucose metabolism in prostate cancer cells : A(13)C stable isotope-resolved metabolomic study", Int J Mol Sci, 18, pp.162~ (2017)
- Li ZY, "Mitochondrial ROS generation for regulation of autophagic pathways in cancer", Biochem Biophys Res Commun, 414, pp.5~8 (2011)
- Csibi A, "The mTORC1", S6K1pathway regulates glutamine metabolism through the eIF4Bdependent control of c-Myc translation, 2014, pp.24, 2274~2280
- Park SY, "Melatonin suppresses tumor angiogenesis by inhibiting HIF-1alpha stabilization under hypoxia", J Pineal Res, 48, pp.178~184 (2010)
- Park JW, "Melatonin down-regulates HIF-1 alpha expression through inhibition of protein translation in prostate cancer cells", J Pineal Res, 46, pp.415~421 (2009)
- Bonello S, "Reactive oxygen species activate the HIF-1alpha promoter via a functional NFkappaB site", Arterioscler Thromb Vasc Biol, 27, pp.755~761 (2007)
- Loureiro R, "Melatonin antiproliferative effects require active mitochondrial function in embryonal carcinoma cells", Oncotarget, 6, pp.17081~17096 (2015)
- Gonzalez A, "Melatonin modulates red-ox state and decreases viability of rat pancreatic stellate cells", Sci Rep, 10, pp.6352~ (2020)
- Guo C, "Oxidative stress, mitochondrial damage and neurodegenerative diseases", Neural Regen Res, 8, pp.2003~2014 (2013)
- Ni HM, "Zonated induction of autophagy and mitochondrial spheroids limits acetaminophen-induced necrosis in the liver", Redox Biol, 1, pp.427~432 (2013)
- Ben-Sahra I, "mTORC1 signaling and the metabolic control of cell growth", Curr Opin Cell Biol, 45, pp.72~82 (2017)
- Ferreira GM, "Melatonin attenuates Her-2, p38 MAPK, p-AKT, and mTOR levels in ovarian carcinoma of ethanol-preferring rats", J Cancer, 5, pp.728~735 (2014)