TY - JOUR
T1 - Melatonin decreases breast cancer metastasis by modulating Rho-associated kinase protein-1 expression
AU - Borin, Thaiz Ferraz
AU - Arbab, Ali Syed
AU - Gelaleti, Gabriela Bottaro
AU - Ferreira, Lívia Carvalho
AU - Moschetta, Marina Gobbe
AU - Jardim-Perassi, Bruna Victorasso
AU - Iskander, Asm
AU - Varma, Nadimpalli Ravi S.
AU - Shankar, Adarsh
AU - Coimbra, Verena Benedick
AU - Fabri, Vanessa Alves
AU - De Oliveira, Juliana Garcia
AU - Zuccari, Debora Aparecida Pires De Campos
N1 - Funding Information:
We thank Jucimara Colombo for revising the manuscript critically and Igor Benedick Coimbra who provided medical writing services and performed language editing. We also thank Fundacao de Amparo a Pesquisa do Estado de Sao Paulo - FAPESP (grants n 2011/13154-0, n 2011/20850-3, n 2012/12114-8, n 2011/18986-4 and n 2011/18987-0) and Fundacao de Apoio a Pesquisa e Extensao de Sao Jose do Rio Preto - FAPERP (grant n 176/2014) which funded this research, Faculdade de Medicina de São Jose do Rio Preto - FAMERP and the Laboratory of Molecular Research in Cancer - LIMC/FAMERP for providing material and structure to carry out this project.
Publisher Copyright:
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
PY - 2016/1/1
Y1 - 2016/1/1
N2 - 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.
AB - 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.
KW - 99mTc-tetrofosmin
KW - MCF-7 cells
KW - MDA-MB-231 cells
KW - Rho-associated kinase protein-1 inhibitor
KW - breast cancer
KW - lung metastasis
KW - melatonin
KW - single photon emission computed tomography
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U2 - 10.1111/jpi.12270
DO - 10.1111/jpi.12270
M3 - Article
C2 - 26292662
AN - SCOPUS:84955212354
SN - 0742-3098
VL - 60
SP - 3
EP - 15
JO - Journal of Pineal Research
JF - Journal of Pineal Research
IS - 1
ER -