Deciphering the Molecular Basis of Melatonin Protective Effects on Breast Cells Treated with Doxorubicin: TWIST1 a Transcription Factor Involved in EMT and Metastasis, a Novel Target of Melatonin

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.

A meta‐analysis of microRNA networks regulated by melatonin in cancer: Portrait of potential candidates for breast cancer treatment

“…We initially performed a systematic meta-analysis to identify miRNA expression profiles targeted by melatonin in experimentally relevant studies. Based on the design criteria for eligibility ( Figure 1), 14 studies [47][48][49][50][51][52][53][54][55][56][57][58][59][60] were selected to investigate the miRNAs expression changes induced by melatonin treatment (Table S1). Among the 46 differentially expressed miRNAs, 29 were upregulated, and 17 were downregulated (Table S2).…”

“…[51][52][53][54] The upregulation of miR-10a, miR-10b, and miR-34a by melatonin is likely due to the inhibition of the TF TWIST1, which plays a role in EMT, metastasis, and angiogenesis in estrogen-dependent breast cancer cells. 54 Upregulated miRNAs by melatonin are linked to inhibition of drug resistance and apoptosis induction, but not autophagy in oral carcinoma cells; these effects are mediated by AKT, c-Jun N-terminal kinase (JNK), and p38. 55 We further document the enhancement of biological processes and protein binding based on our interactome analysis.…”

A New and Integral Approach to the Etiopathogenesis and Treatment of Breast Cancer based upon its Hydrogen Ion Dynamics

“…cell-signaling pathways that are key for the proliferation and survival of BC cells, as well as for metastasis and resistance to anti-cancer drugs [217,224,225]. Otherwise, traditional oncology has clearly shown that antiestrogens are an effective measure in the treatment of ER+ BC, using either Tamoxifen or Letrozole.…”

<p>ERα, A Key Target for Cancer Therapy: A Review</p>

“…ERs can be activated when cells are exposed to estrogen. [7][8][9] Emerging evidence shows that the activation of ERs is highly associated with cancer formation and metastasis, [10][11][12] extracellular matrix (ECM) remodeling 2,13 and drug resistance. [14][15][16][17] Here, we focus on providing a comprehensive understanding of ERα.…”