Regulation of cancer cell glucose metabolism is determinant for cancer cell fate after melatonin administration

• Published in: Journal of cellular physiology 2021-01, Vol.236 (1), p.27-40
• Main Authors: Rodríguez, Carmen, Puente‐Moncada, Noelia, Reiter, Russel J., Sánchez‐Sánchez, Ana M., Herrera, Federico, Rodríguez‐Blanco, Jezabel, Duarte‐Olivenza, Cristina, Turos‐Cabal, María, Antolín, Isaac, Martín, Vanesa
• Format: Article
• Language: English
• Subjects: aerobic glycolysis; Anticancer properties; Antitumor activity; Cancer; Cell death; Cell fate; Gluconeogenesis; Glucose; Glucose metabolism; Glycolysis; Hypoxia; Low concentrations; Melatonin; melatonin cytotoxicity; Metabolic pathways; Metabolism; Oxidative phosphorylation; Pentose; Pentose phosphate pathway; Phosphorylation; Side effects; TCA cycle; Tricarboxylic acid cycle; tumor metabolism; Tumors
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.29886

Several oncogenic pathways plus local microenvironmental conditions, such as hypoxia, converge on the regulation of cancer cells metabolism. The major metabolic alteration consists of a shift from oxidative phosphorylation as the major glucose consumer to aerobic glycolysis, although most of cancer cells utilize both pathways to a greater or lesser extent. Aerobic glycolysis, together with the directly related metabolic pathways such as the tricarboxylic acid cycle, the pentose phosphate pathway, or gluconeogenesis are currently considered as therapeutic targets in cancer research. Melatonin has been reported to present numerous antitumor effects, which result in a reduced cell growth. This is achieved with both low and high concentrations with no relevant side effects. Indeed, high concentrations of this indolamine reduce proliferation of cancer types resistant to low concentrations and induce cell death in some types of tumors. Previous work suggest that regulation of glucose metabolism and other related pathways play an important role in the antitumoral effects of high concentration of melatonin. In the present review, we analyze recent work on the regulation by such concentrations of this indolamine on aerobic glycolysis, gluconeogenesis, the tricarboxylic acid cycle and the pentose phosphate pathways of cancer cells. Melatonin attacks at least four metabolic pathways previously reported to be therapeutic targets in cancer. There is a reduction of both aerobic glycolysis and metabolic flux in the TCA cycle after treatment with melatonin in cancer cells in which this indolamine results cytotoxic. Such alterations may cause a shortage of energy and an ROS rise and consequently cell death. Inhibition of the pentose phosphate pathway and activation of gluconeogenesis can also be involved in the induction of cell death.