Clock genes and the role of melatonin in cancer cells: an overview

Abstract

Circadian rhythms control most biological processes in every organism and their disruption or an aberrant function in the expression of clock genes are associated with a number of cancers including some hormone-dependent and independent cancers. The processes involved in carcinogenesis and tumor progression are complex, but understanding the daily profiles of the core clock genes and their clock-controlled genes is essential to evaluate specifically the molecular program of the cancer phenotype; this may be helpful in providing a more realistic strategy for both diagnosis and treatment during the course of the disease. Because melatonin production and secretion oscillates rhythmically through the light:dark cycle and is related to the circadian machinery genes (Clock, Bmal1, Periods, and Cryptochromes), its regulatory role on clock genes in cancer cells may bring additional evidence regarding the mechanism(s) by which melatonin is involved. Mechanistically, melatonin acts via proteasome inhibition and sirtuins to indirectly modulate clock genes in cancer; however, melatonin seems to be capable of directly altering the expression of clock genes to affect cancer development. Depending on cancer cell type, melatonin might up or downregulate specific clock genes to control cell cycle, survival, repair mechanisms, etc. In parallel, melatonin exerts pro-apoptotic, anti-proliferative and pro-oxidative effects, metabolic shifting, reduction in neovasculogenesis and inflammation, and restores chemosensitivity of cancer cells. Finally, melatonin improves the life quality of patients. This review focuses on the main functions of melatonin on clock genes, and reviews, from a clinical and experimental standpoint, how melatonin regulates the expression of clock genes in some prevalent cancer types such as breast, prostate, liver, and colon cancers, leukemia and melanoma. We further emphasized possible signaling mechanisms whereby melatonin interferes with clockwork genes and circadian-controlled genes within cancer cells.

Hypoxia, metabolism, and the circadian clock: new links to overcome radiation resistance in high-grade gliomas

“…Moreover, melatonin, the secretory product of pineal gland, has also been recently reported to promote the synthesis of acetyl-CoA from pyruvate by inhibiting PDK in breast cancer models [160]. The inhibitory effect of melatonin on PDK not only reverses the Warburg effect, reduces tumor mass, and improves the sensitivity of tumor cells to chemoradiotherapy [160,161], it also leads to a circadian rhythm of glucose metabolism in these cancer cells [162,163].…”

Melatonin increases overall survival of prostate cancer patients with poor prognosis after combined hormone radiation treatment

“…A number of epidemiological studies have shown the clinical effectiveness of melatonin in reducing both the risk of developing PCa and its aggressiveness [1,14]. In vitro/in vivo studies demonstrate various mechanisms of inhibition of tumor proliferation of prostate adenocarcinoma cells both by enhancing apoptosis and cytoreduction, and by reducing tumor potential and angiogenesis [6,7,15,16]. Of particular interest are the works demonstrating positive results of melatonin use in treatment of castrate-resistant metastatic PCa, when the possibilities of most available drugs have already been exhausted.…”

Melatonin Promotes Uterine and Placental Health: Potential Molecular Mechanisms

“…A plethora of recent studies has documented that melatonin synchronizes the clockwork machinery in healthy and damaged cells, either up or downregulating specific clock genes to maintain optimal physiology [29][30][31]. Through its multiple actions, melatonin works as a circadian regulator, natural antioxidant, and anti-inflammatory and oncostatic agent, like many other functions [32][33][34].…”

“…Melatonin receptors are formed by seven transmembrane domains coupled to high-affinity G protein, termed melatonin receptor 1 (MT1) (also called MTNR1A or Mel1a), MT2 (also called MTNR1B or Mel1b), and MT3 (identified as quinone reductase II enzyme); they often act as homo or heterodimers to reduce the levels of cAMP and cGMP thereby increasing phosphorylation of other proteins [35]. Due to its amphiphilicity, melatonin crosses the cell membrane thus interacting with intracellular molecules via different signaling pathways; these include scavenger functions, binding to calmodulin, and many other molecules [31]. The statement that melatonin binds to RORα and RORγ has been previously investigated and they found a lack of effect of melatonin and its derivatives on RORα and RORγ activities, thereby showing by docking analyses that these nuclear receptors have no high-affinity for melatonin [36,37].…”