Melatonin decreases breast cancer metastasis by modulating Rho-associated kinase protein-1 expression

Thaiz Ferraz Borin, Ali Syed Arbab, Gabriela Bottaro Gelaleti, Lívia Carvalho Ferreira, Marina Gobbe Moschetta, Bruna Victorasso Jardim-Perassi, Asm Iskander, Nadimpalli Ravi S. Varma, Adarsh Shankar, Verena Benedick Coimbra, Vanessa Alves Fabri, Juliana Garcia De Oliveira, Debora Aparecida Pires De Campos Zuccari

Research output: Contribution to journalArticle

71 Scopus citations

Abstract

The occurrence of metastasis, an important breast cancer prognostic factor, depends on cell migration/invasion mechanisms, which can be controlled by regulatory and effector molecules such as Rho-associated kinase protein (ROCK-1). Increased expression of this protein promotes tumor growth and metastasis, which can be restricted by ROCK-1 inhibitors. Melatonin has shown oncostatic, antimetastatic, and anti-angiogenic effects and can modulate ROCK-1 expression. Metastatic and nonmetastatic breast cancer cell lines were treated with melatonin as well as with specific ROCK-1 inhibitor (Y27632). Cell viability, cell migration/invasion, and ROCK-1 gene expression and protein expression were determined in vitro. In vivo lung metastasis study was performed using female athymic nude mice treated with either melatonin or Y27832 for 2 and 5 wk. The metastases were evaluated by X-ray computed tomography and single photon emission computed tomography (SPECT) and by immunohistochemistry for ROCK-1 and cytokeratin proteins. Melatonin and Y27632 treatments reduced cell viability and invasion/migration of both cell lines and decreased ROCK-1 gene expression in metastatic cells and protein expression in nonmetastatic cell line. The numbers of 'hot' spots (lung metastasis) identified by SPECT images were significantly lower in treated groups. ROCK-1 protein expression also was decreased in metastatic foci of treated groups. Melatonin has shown to be effective in controlling metastatic breast cancer in vitro and in vivo, not only via inhibition of the proliferation of tumor cells but also through direct antagonism of metastatic mechanism of cells rendered by ROCK-1 inhibition. When Y27632 was used, the effects were similar to those found with melatonin treatment.

Original languageEnglish (US)
Pages (from-to)3-15
Number of pages13
JournalJournal of Pineal Research
Volume60
Issue number1
DOIs
StatePublished - Jan 1 2016

Keywords

  • 99mTc-tetrofosmin
  • MCF-7 cells
  • MDA-MB-231 cells
  • Rho-associated kinase protein-1 inhibitor
  • breast cancer
  • lung metastasis
  • melatonin
  • single photon emission computed tomography

ASJC Scopus subject areas

  • Endocrinology

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  • Cite this

    Borin, T. F., Arbab, A. S., Gelaleti, G. B., Ferreira, L. C., Moschetta, M. G., Jardim-Perassi, B. V., Iskander, A., Varma, N. R. S., Shankar, A., Coimbra, V. B., Fabri, V. A., De Oliveira, J. G., & Zuccari, D. A. P. D. C. (2016). Melatonin decreases breast cancer metastasis by modulating Rho-associated kinase protein-1 expression. Journal of Pineal Research, 60(1), 3-15. https://doi.org/10.1111/jpi.12270