Molecular mechanisms of melatonin's inhibitory actions on breast cancers

Abstract

Melatonin is involved in many physiological functions and it plays an important role in many pathological processes as well. Melatonin has been shown to reduce the incidence of experimentally induced cancers and can significantly inhibit the growth of some human tumors, namely hormone-dependent cancers. The anticancer effects of melatonin have been observed in breast cancer, both in in vivo with models of chemically induced rat mammary tumors, and in vitro studies on human breast cancer cell lines. Melatonin acts at different physiological levels and its antitumoral properties are supported by a set of complex, different mechanisms of action, involving apoptosis activation, inhibition of proliferation, and cell differentiation.

Fig. 1

Melatonin and estrogens have different actions on breast cancer cells. Estradiol stimulates cell proliferation, while reducing differentiation processes; conversely, melatonin promotes differentiation and reduces breast cancer cell proliferation

Fig. 2

Melatonin interacts with the Ca⁺⁺/calmodulin signaling pathway, either by modifying the intracellular accumulation of Ca⁺⁺ or by means of a direct interaction with calmodulin. Calmodulin interacts with ER, stimulating the phosphorylation of the receptor and enhancing the binding of the estradiol–ER complex to ERE (estrogen response elements). Estrogens activate adenylate cyclase and increase cAMP; on the contrary, melatonin, after its binding to MT1, inhibits adenylate cyclase and reduces cAMP

Fig. 3

Melatonin significantly inhibits cancer proliferation by increasing the p53/MDM2 and Akt/Akt-P ratios. The p53 gene activates the expression of p21, which inhibits cyclin-dependent kinases, thus leading to cell cycle arrest. In addition, melatonin induces apoptosis in MCF-7 cancer cells. Melatonin-mediated early apoptosis is a caspase-independent process, involving the apoptosis-inducing factor (AIF). Melatonin-induced late apoptosis is TGFβ-1 and caspase-dependent process. During late apoptosis, activated caspase-9, -7, and cleaved-PARP increase significantly, concomitant with a down-regulation of the Bcl/Bax ratio. By adding anti-TGFβ-1 neutralizing antibodies, growth inhibition and late apoptosis triggered by melatonin are inhibited

Fig. 4

After binding to the MT1 receptor, melatonin reduces MDM2 levels, thus allowing p53 to escape from the autoregulatory loop. The modified p53/MDM2 ratio triggers the apoptosis cascade involving both caspases-dependent and caspases-independent pathways. In addition, melatonin increases mitochondrial membrane depolarization, releasing cytochrome C and apoptosis inducing factor (AIF). Melatonin is likely to inhibit AKT phosphorylation and subsequently the MAPK-related pathways