Anti-Warburg Effect of Melatonin: A Proposed Mechanism to Explain its Inhibition of Multiple Diseases

Abstract

Glucose is an essential nutrient for every cell but its metabolic fate depends on cellular phenotype. Normally, the product of cytosolic glycolysis, pyruvate, is transported into mitochondria and irreversibly converted to acetyl coenzyme A by pyruvate dehydrogenase complex (PDC). In some pathological cells, however, pyruvate transport into the mitochondria is blocked due to the inhibition of PDC by pyruvate dehydrogenase kinase. This altered metabolism is referred to as aerobic glycolysis (Warburg effect) and is common in solid tumors and in other pathological cells. Switching from mitochondrial oxidative phosphorylation to aerobic glycolysis provides diseased cells with advantages because of the rapid production of ATP and the activation of pentose phosphate pathway (PPP) which provides nucleotides required for elevated cellular metabolism. Molecules, called glycolytics, inhibit aerobic glycolysis and convert cells to a healthier phenotype. Glycolytics often function by inhibiting hypoxia-inducible factor-1α leading to PDC disinhibition allowing for intramitochondrial conversion of pyruvate into acetyl coenzyme A. Melatonin is a glycolytic which converts diseased cells to the healthier phenotype. Herein we propose that melatonin’s function as a glycolytic explains its actions in inhibiting a variety of diseases. Thus, the common denominator is melatonin’s action in switching the metabolic phenotype of cells.

Regulation of Cancer Metabolism by Deubiquitinating Enzymes: The Warburg Effect

“…The phosphorylated AKT separates from the cell membrane, causing intracellular reactions with the mTORC-containing substrates. AKT promotes lipid biosynthesis and glucose transport to cancer cells with improved glycolysis through activation of mTOR [24]. The PI3K/AKT signaling pathway promotes the breakdown and uptake of glucose and lactic acid production, thus playing an important role in the metabolic reprogramming of cancer cells [25].…”

Metabolic Anti-Cancer Effects of Melatonin: Clinically Relevant Prospects

“…New molecular insights beyond metabolic reprogramming introduce new opportunities to target essential steps of cancer-associated energetic processes. Melatonin affects steps associated with the Warburg phenotype and suppresses the switch from OXPHOS to aerobic glycolysis [ 12 ].…”

“…Moreover, melatonin has oncostatic effects by stimulating apoptosis, regulation of survival signaling, suppression of metastasis and angiogenesis and on the epigenetic machinery contributing to the malignant transformation demonstrated in vitro and in vivo [ 8 , 9 , 10 , 11 ]. Significantly, melatonin can attenuate the metabolic reprogramming of cancer cells [ 12 , 13 ]. Indeed, melatonin exerts a wide range of different effects, and its functional chemical groups play a key role in the induced oncostatic properties.…”

Melatonergic index as a prognostic biomarker of reproductive organ cancers: correlations with metabolic parameters as well as clock genes PER1 and TIMELESS

“…The notion that the expression of melatoninconverting enzyme is correlated with the expression of these metabolic enzymes brings up a possible genetic and functional interdependence associated with these tumor types. Importantly, melatonin functions as a glycolytic agent by changing the tumor cell phenotype to a healthier phenotype (54). In this context, numerous observations point to melatonin synthesized in the mitochondria of all healthy cells but not, or at much lower levels, in cancerous cells.…”