Circadian and non-circadian melatonin: influences on glucose metabolism in cancer cells

Russel J. Reiter; Ramaswamy  Sharma; Qiang Ma; Sergio Rosales-Corral; Walter  Manucha

Authors

Russel J. Reiter Department of Cell Systems and Anatomy, UT Health San Antonio, Texas 78229, USA and Department of Molecular Genetics, University of Lodz, Lodz, 90-137 Łódź, Poland
Ramaswamy Sharma Department of Cell Systems and Anatomy, UT Health San Antonio, Texas 78229, USA
Qiang Ma Department of Cell Systems and Anatomy, UT Health San Antonio, Texas 78229, USA
Sergio Rosales-Corral Centro de Investigacion Biomedica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Jalisco, Mexico
Walter Manucha Departamento de Patología, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza, Argentina

Keywords:

aerobic glycolysis, angiogenesis, cancer metastasis, glucose metabolism, Hypoxia inducible factor-1α, pyruvate dehydrogenase kinase

Abstract

This review considers the role of melatonin as an oncostatic agent and particularly as to how it relates to the mechanisms by which melatonin regulates glucose metabolism in cancer cells. Many tumor cells adopt a means of glucose utilization that is different from that of healthy cells. Thus, these cancer cells rapidly take up and metabolize glucose and after it is converted to pyruvate, they accelerate the production of lactate which is abundantly released into the circulation. The change in metabolism that cancer cells makes is referred to as aerobic glycolysis. The switch to aerobic glycolysis affords cancer cells major advantages in terms of an accelerated rate of ATP production and the synthesis of abundant molecular building blocks required for rapid proliferation, invasion, and metastasis. In normal cells, the bulk of the pyruvate formed is shunted into the mitochondria for conversion to acetyl-CoA. Melatonin is both produced and released in a circadian manner from the pineal gland and likely by the mitochondria of all normal cells in a non-circadian manner. In cancer cells, melatonin forces them to abandon aerobic glycolysis and function phenotypically as a normal cell by upregulating the enzyme, pyruvate dehydrogenase complex, that catalyzes pyruvate to acetyl-CoA; this is presumably achieved by the direct or indirect inhibition of pyruvate dehydrogenase kinase, which normally downregulates pyruvate dehydrogenase complex. By depriving cancer cells of aerobic glycolysis, melatonin reverts them to a normal cell phenotype thereby reducing the rapid cell proliferation and aggressive nature of cancer cells.

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