Melatonin Regulates Angiogenic Factors under Hypoxia in Breast Cancer Cell Lines

Abstract

Angiogenesis is the process of new blood vessel formation, regulated by a number of pro- and antiangiogenic factors and usually begins in response to hypoxia. Exogenous administration of melatonin has shown numerous anti-tumor effects and appears to inhibit tumor angiogenesis. However, many factors involved in the anti-angiogenic effect of melatonin are still under investigation. Here, we evaluate the effects of melatonin on cell viability and expression of angiogenic factors in MCF-7 and MDA-MB-231 breast cancer cells under hypoxic conditions. Cell viability was investigated by MTT and gene and protein expression of the hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF-A) were verified by qPCR and immunocytochemistry after melatonin treatment (1 mM) under hypoxic conditions. Additionally, a protein array with 20 different cytokines/factors was performed on tumor cell lysates. The results showed that 1 mM of melatonin reduced the viability of MCF-7 and MDA-MB-231 cells (p < .05). This treatment also decreased both gene and protein expression of HIF-1α and VEGF-A under hypoxic conditions (p < .05). Among the proteins evaluated by protein array, melatonin treatment during hypoxia reduced VEGF-C, VEGFR receptors (VEGFR2 and VEGFR3), matrix metalloproteinase 9 (MMP9) and Angiogenin in MCF-7 cells. In MDA-MB-231 cells, a significant decrease was observed in VEGFR2, epidermal growth factor receptor (EGFR) and Angiogenin (p < .05). Taken together, these results showed that melatonin acts in the regulation of angiogenic factors in breast tumor cells and suggests an anti-angiogenic activity, particularly under hypoxic conditions.

Melatonin Reduces Angiogenesis in Serous Papillary Ovarian Carcinoma of Ethanol-Preferring Rats

“…Consistent with our results, a recent study demonstrated that melatonin reduced the expression of VEGFR2 in breast cancer cells (MCF-7 and MDA-MB-231 cell lines), and also in mammary tumors of athymic nude mice [27,52]. …”

Melatonin for the prevention and treatment of cancer

“…Early studies reported that melatonin produced antiproliferative effect in breast cancer cells in vitro [47], and inhibited the growth of mammary tumors in rats [48, 49]. Afterwards, different mechanisms of melatonin's anticancer effects were identified successively, such as inducing apoptosis [50], antiestrogenic effect through ERα-signaling pathway and inhibiting aromatase activity [51–53], modulation of melatonin receptors [54], and inhibition on invasion [55] and angiogenesis [56]. …”

“…For breast cancer, 1 nM melatonin reduced the viability of hypoxic MCF-7 and MDA-MB-231 human breast cancer cells and decreased both gene and protein expression of HIF-1α and VEGF-A ( p < 0 .05), indicating an anti-angiogenesis effect [56]. Additionally, Alvarez-Garcia et al .…”

Melatonin as a potential anticarcinogen for non-small-cell lung cancer

“…However, the mechanisms of melatonin's antiangiogenic in any tumor including NSCLC are still unclear. Numerous studies have documented that melatonin exhibits antiangiogenic actions, in part, by downregulating VEGF and HIF-1α in several cancers via different mechanisms; the cancer types included breast [16, 149], prostate [150–152], colon [153, 154], liver [155], and pancreatic cancer [156, 157]. These studies may provide reference for the future work in the NSCLC research field.…”