Abstract
Melatonin mitigates cancer initiation, progression and metastasis through inhibition of both the synthesis of estrogens and the transcriptional activity of the estradiol-ER (Estrogen receptor) complex in the estrogen-dependent breast cancer cell line MCF-7. Moreover, melatonin improves the sensitivity of MCF-7 to chemotherapeutic agents and protects against their side effects. It has been described that melatonin potentiates the anti-proliferative effects of doxorubicin; however, the molecular changes involving gene expression and the activation/inhibition of intracellular signaling pathways remain largely unknown. Here we found that melatonin enhanced the anti-proliferative effect of doxorubicin in MCF-7 but not in MDA-MB-231 cells. Strikingly, doxorubicin treatment induced cell migration and invasion, and melatonin effectively counteracted these effects in MCF-7 but not in estrogen-independent MDA-MB-231 cells. Importantly, we describe for the first time the ability of melatonin to downregulate TWIST1 (Twist-related protein 1) in estrogen-dependent but not in estrogen-independent breast cancer cells. Combined with doxorubicin, melatonin inhibited the activation of p70S6K and modulated the expression of breast cancer, angiogenesis and clock genes. Moreover, melatonin regulates the levels of TWIST1-related microRNAs, such as miR-10a, miR-10b and miR-34a. Since TWIST1 plays a pivotal role in the epithelial to mesenchymal transition, acquisition of metastatic phenotype and angiogenesis, our results suggest that inhibition of TWIST1 by melatonin might be a crucial mechanism of overcoming resistance and improving the oncostatic potential of doxorubicin in estrogen-dependent breast cancer cells.
Highlights
Melatonin is an indolamine mainly secreted by the pineal gland during the night
The pineal hormone controls the transcriptional activity of the estradiol-estrogen receptor complex, behaving as a selective estrogen receptor modulator (SERM), and diminishes the production of estrogens through the regulation of the enzymes involved in estrogen activation/inactivation, behaving as a selective estrogen enzyme modulator (SEEM) [9,10,11]
We first investigated the ability of melatonin to modulate the anti-proliferative effects of doxorubicin, by using two different breast cancer cell lines: the hormone-dependent MCF-7 and the hormone-independent MDA-MB-231
Summary
Melatonin is an indolamine mainly secreted by the pineal gland during the night. It is a multitasking molecule acting through various mechanisms (e.g., G-protein coupled membrane receptors, interactions with orphan receptors or cytosolic molecules such as calmodulin), thereby playing multipleCancers 2019, 11, 1011; doi:10.3390/cancers11071011 www.mdpi.com/journal/cancersCancers 2019, 11, 1011 different roles as an antioxidant, immunomodulatory, endocrine regulatory molecule, circadian rhythm synchronizer or anticancer agent controlling cell physiology [1,2,3]. Melatonin is an indolamine mainly secreted by the pineal gland during the night. It is a multitasking molecule acting through various mechanisms (e.g., G-protein coupled membrane receptors, interactions with orphan receptors or cytosolic molecules such as calmodulin), thereby playing multiple. Cancers 2019, 11, 1011 different roles as an antioxidant, immunomodulatory, endocrine regulatory molecule, circadian rhythm synchronizer or anticancer agent controlling cell physiology [1,2,3]. The oncostatic actions of melatonin have been largely described in hormone-dependent tumors, either when administered alone or in combination with chemotherapeutic agents [6,7,8]. The pineal hormone controls the transcriptional activity of the estradiol-estrogen receptor complex, behaving as a selective estrogen receptor modulator (SERM), and diminishes the production of estrogens through the regulation of the enzymes involved in estrogen activation/inactivation, behaving as a selective estrogen enzyme modulator (SEEM) [9,10,11].
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