Melatonin Regulates Angiogenic Factors under Hypoxia in Breast Cancer Cell Lines

Author(s):

Bruna Victorasso Jardim-Perassi, Mateus Repolês Lourenço, Gabriel Mandarini Doho, Ingrid Helen Grígolo, Gabriela Bottaro Gelaleti, Lívia Carvalho Ferreira, Thaiz Ferraz Borin, Marina Gobbe Moschetta and Debora Aparecida Pires de Campos Zuccari   Pages 347 - 358 ( 12 )

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.

Keywords:

Angiogenesis, breast neoplasms, cell hypoxia, cell line, gene expression, melatonin, vascular endothelial growth factors.

Affiliation:

, , , , , , , , Laboratório de Investigação Molecular no Câncer (LIMC), Faculdade de Medicina de São José do Rio Preto/FAMERP. Avenida Brigadeiro Faria Lima, 5416, Vila São Pedro, 15090-000 São José do Rio Preto, SP, Brazil.

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