Inhibition of mitochondrial pyruvate dehydrogenase kinase: a proposed mechanism by which melatonin causes cancer cells to overcome cytosolic glycolysis, reduce tumor biomass and reverse insensitivity to chemotherapy
Melatonin and cancer cell glycolysis
Keywords: oxidative phosphorylation, N-acetyltransferase, pyruvate kinase, acetyl-CoA, aerobic glycolysis, chemotherapy, melatonin
Abstract
This review presents a hypothesis to explain the role of melatonin in regulating glucose metabolism in cancer cells. Many cancer cells use cytosolic glycolysis (the Warburg effect) to produce energy (ATP). Under these conditions, glucose is primarily converted to lactate which is released into the blood in large quantities. The Warburg effect gives cancer cells advantages in terms of enhanced macromolecule synthesis required for accelerated cellular proliferation, reduced cellular apoptosis which enhances tumor biomass and a greater likelihood of metastasis. Based on available data, high circulating melatonin levels at night serve as a signal for breast cancer cells to switch from cytosolic glycolysis to mitochondrial glucose oxidation and oxidative phosphorylation for ATP production. In this situation, melatonin promotes the synthesis of acetyl-CoA from pyruvate; we speculate that melatonin does this by inhibiting the mitochondrial enzyme pyruvate dehydrogenase kinase (PDK) which normally inhibits pyruvate dehydrogenase complex (PDC), the enzyme that controls the pyruvate to acetyl-CoA conversion. Acetyl-CoA has several important functions in the mitochondria; it feeds into the citric acid cycle which improves oxidative phosphorylation and, additionally, it is a necessary co-factor for the rate limiting enzyme, arylalkylamine N-acetyltransferase, in mitochondrial melatonin synthesis. When breast cancer cells are using cytosolic glycolysis (during the day) they are of the cancer phenotype; at night when they are using mitochondria to produce ATP via oxidative phosphorylation, they have a normal cell phenotype. If this day:night difference in tumor cell metabolism is common in other cancers, it indicates that these tumor cells are only cancerous part of the time. We also speculate that high nighttime melatonin levels also reverse the insensitivity of tumors to chemotherapy.
References
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17: E843.
17. Gonzalez-Gonzalez A, Rueda-Revilla N, Sanchez-Barcelo EJ (2019) Clinical uses of melatonin: evaluation of human clinical trials on cancer treatment. Melatonin Res. 2: 47-69.
18. Blask DE, Dauchy RT, Dauchy EM, et al. (2014) Light exposure at night disrupts host/cancer circadian regulatory dynamics: impact on the Warburg effect, lipid signaling and tumor growth prevention. PLoS One 9: e102776.
19. Reiter RJ, Rosales-Corral S, Tan DX, et al. (2017) Melatonin as a mitochondria-targeted antioxidant: one of evolution’s best ideas. Cell. Mol. Life Sci. 74: 3863-3881.
20. Tan DX, Reiter RJ (2019) Mitochondria: the birth place, battle ground and the site of melatonin metabolism in cells. Melatonin Res. 2: 44-66.
21. Dauchy RT, Wren-Dail MA, Dupepe LM, et al. (2018) Effect of daytime blue-enriched LED on the nighttime circadian melatonin inhibition of hepatoma 7288CTC Warburg effect and progression. Comp. Med. 68: 269-279.
22. Mayo JC, Sainz RM, Gonzalez-Menendez P, et al. (2017) Melatonin transport into mitochondria. Cell. Mol. Life Sci. 74: 3927-3940.
23. Acuna-Castroviejo D, Noguera-Navarro MT, Reiter RJ, et al. (2018) Melatonin actions in the heart: more than a hormone. Melatonin Res. 1: 21-26.
24. Jou MJ, Peng TI, Reiter RJ, et al. (2004) Visualization of the antioxidative effects of melatonin at the mitochondrial level during oxidative stress-induced apoptosis of rat brain astrocytes. J. Pineal Res. 37: 55-70.
25. Jou MJ, Peng TI, Yu PZ, et al. (2007) Melatonin protects against common deletion of mitochondrial DNA-augmented mitochondrial oxidative stress and apoptosis.
J. Pineal Res. 43: 389-403.
26. Ressmeyer AR, Mayo JC, Zelosko V, et al. (2004) Antioxidant properties of the melatonin metabolite N1-acetyl-5-methoxykynuramine (AMK): scavenging of free radicals and prevention of protein destruction. Redox Rep. 8: 205-213.
27. Manchester LC, Coto-Montes A, Boga JA, et al. (2015) Melatonin: an ancient molecule that makes oxygen metabolically tolerable. J. Pineal Res. 59: 403-419.
28. Martin M, Macias M, Leon J, et al. (2002) Melatonin increases the activity of the oxidative phosphorylation enzymes and the production of ATP in rat brain and liver mitochondria. Int. J. Biochem. Cell Biol. 34: 348-357.
29. Venegas C, Garcia JA, Escames G, et al. (2012) Extrapineal melatonin: analysis of its subcellular distribution and daily fluctuations. J. Pineal Res. 52: 217-227.
30. Hevia D, Sainz RM, Blanco D, et al. (2008) Melatonin uptake in prostate cancer cells: intracellular transport versus simple passive diffusion. J. Pineal Res. 45: 247-257.
31. Hevia D, Gonzalez-Menendez P, Quiros-Gonzalez I, et al. (2015) Melatonin uptake through glucose transporters: a new target for melatonin inhibition of cancer.
J. Pineal Res. 58: 234-250.
32. Huo X, Wang C, Yu Z, et al. (2017) Human transporters, PEPT1/2 facilitate melatonin transportation into mitochondria of cancer cells: an implication of the therapeutic potential. J. Pineal Res. 62: e12390.
33. Boutin JA (2016) Quinone reductase 2 as a promising target of melatonin therapeutic actions. Expert Opin. Ther. Targets 20: 303-317.
34. Suofu Y, Li W, Jean-Alphonse FG, et al. (2017) Dual role of mitochondria in producing melatonin and driving GPCR signaling to block cytochrome c release. Proc. Natl. Acad. Sci. USA 114: E7997-E8006.
35. Hardeland R (2018) Recent findings in melatonin research and their relevance to the CNS. Cent. Nerv. Sept. Agents Med. Chem. 18: 102-114.
36. Reiter RJ, Paredes SD, Korkmaz A, et al. (2008) Melatonin combats molecular terrorism at the mitochondrial level. Interdiscip. Toxicol. 1: 137-149.
37. Reiter RJ, Tan DX, Galano A (2014) Melatonin: exceeding expectations. Physiology (Bethesda) 29: 325-333.
38. Manchester LC, Poeggeler B, Alvares FL, et al. (1995) Melatonin immunoreactivity in the photosynthetic prokaryote Rhodospirillum rubrum: implications for an ancient antioxidant system. Cell. Mol. Biol. Res. 41: 391-395.
39. Lee HJ, Back K (2019) 2-hydroxymelatonin confers tolerance against combined cold and drought stress in tobacco, tomato, and cucumber as a potent anti-stress compound in the evolution of land plants. Melatonin Res. 2: 36-47.
40. Tan DX, Manchester LC, Liu X, et al. (2013) Mitochondria and chloroplasts as the original sites of melatonin synthesis: a hypothesis related to melatonin’s primary function and evolution in eukaryotes. J. Pineal Res. 54: 127-138.
41. Kerenyi NA, Sotonyi P, Somogyi E (1975) Localizing acetyl-serotonin transferase by electron microscopy. Histochemistry 44: 77-80.
42. He C, Wang J, Zhang Z, et al. (2016) Mitochondria synthesize melatonin to ameliorate its function and improve mice oocyte’s quality under in vitro conditions. Int. J. Mol. Sci. 17: 939-955.
43. Yang M, Tao J, Wu H, et al. (2019) Aanat knockdown and melatonin supplementation in embryo development: involvement of mitochondrial function and DNA methylation. Antioxid. Redox Signal. 30: 2050-2065.
44. Wang L, Feng C, Zheng X, et al. (2017) Plant mitochondria synthesize melatonin and enhance the tolerance of plants to drought stress. J. Pineal Res. 63: e12429.
45. Byeon Y, Lee H, Choi D, et al. (2015) Chloroplast-encoded serotonin N-acetyltransferase in the red alga Pyropia yezoensis: gene transition to nucleus from chloroplasts. J. Exp. Bot. 66: 709-717.
46. Zheng X, Tan DX, Allan AC, et al. (2017) Chloroplastic biosynthesis of melatonin and its involvement in protection in plants from salt stress. Sci. Rep. 7: 41236.
47. Reiter RJ, Tan DX, Rosales-Corral S, et al. (2018) Melatonin mitigates mitochondrial meltdown: interactions with SIRT3. Int. J. Mol. Sci. 19: E2439.
48. Cardinali DP, Vigo DE (2017) Melatonin, mitochondria, and the metabolic syndrome. Cell. Mol. Life Sci. 74: 3941-3954.
49. Acuna-Castroviejo D, Rahim I, Acuna-Fernandez C, et al. (2017) Melatonin, clock genes and mitochondria in sepsis. Cell. Mol. Life Sci. 74: 3695-3988.
50. Slominski AT, Zmijewski MA, Semak J, et al. (2017) Melatonin, mitochondria, and the skin. Cell. Mol. Life Sci. 74: 3913-3925.
51. Galano A, Tan DX, Reiter RJ (2018) Melatonin: a versatile protector against oxidative DNA damage. Molecules 23: E530.
52. Dominguez-Rodriguez A, Abreu-Gonzalez P, Chen Y (2019) Cardioprotection and effects of melatonin administration on cardiac ischemia-reperfusion: insight from clinical studies. Melatonin Res. 2: 100-106.
53. Zhao D, Yu Y, Shen Y. et al. (2019) Melatonin synthesis and function: evolutionary history in animals and in plants. Front. Endocrinol. 10: 249.
54. Guaragnella N, Giannattasio S, Moro L (2014) Mitochondrial dysfunction in cancer chemoresistance. Biochem. Pharmacol. 92: 62-72.
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Published
2019-08-31
How to Cite
[1]
Reiter, R.J., Sharma, R., Ma, Q., Rosales-Corral, S., Acuna-Castroviejo, D. and Escames, G. 2019. Inhibition of mitochondrial pyruvate dehydrogenase kinase: a proposed mechanism by which melatonin causes cancer cells to overcome cytosolic glycolysis, reduce tumor biomass and reverse insensitivity to chemotherapy. Melatonin Research. 2, 3 (Aug. 2019), 105-119. DOI:https://doi.org/https://doi.org/10.32794/mr11250033.
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