title: Melatonin decreases breast cancer metastasis by modulating Rho-associated kinase protein-1 expression.
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.
authors: Laboratory of Molecular Investigation of Cancer - LIMC, Department of Molecular Biology, Faculdade de Medicina de Sao Jose do Rio Preto - FAMERP, Sao Jose do Rio Preto, SP, Brazil.
authors: Thaiz Ferraz
authors: TF
authors: Borin
authors: Tumor angiogenesis laboratory, Cancer Center, Georgia Regents University, Augusta, GA, USA.
authors: Ali Syed
authors: AS
authors: Arbab
authors: Laboratory of Molecular Investigation of Cancer - LIMC, Department of Molecular Biology, Faculdade de Medicina de Sao Jose do Rio Preto - FAMERP, Sao Jose do Rio Preto, SP, Brazil.|Universidade Estadual Paulista Julio de Mesquita Filho - IBILCE/UNESP, Sao Jose do Rio Preto, SP, Brazil.
authors: Gabriela Bottaro
authors: GB
authors: Gelaleti
authors: Laboratory of Molecular Investigation of Cancer - LIMC, Department of Molecular Biology, Faculdade de Medicina de Sao Jose do Rio Preto - FAMERP, Sao Jose do Rio Preto, SP, Brazil.|Universidade Estadual Paulista Julio de Mesquita Filho - IBILCE/UNESP, Sao Jose do Rio Preto, SP, Brazil.
authors: Lívia Carvalho
authors: LC
authors: Ferreira
authors: Laboratory of Molecular Investigation of Cancer - LIMC, Department of Molecular Biology, Faculdade de Medicina de Sao Jose do Rio Preto - FAMERP, Sao Jose do Rio Preto, SP, Brazil.
authors: Marina Gobbe
authors: MG
authors: Moschetta
authors: Laboratory of Molecular Investigation of Cancer - LIMC, Department of Molecular Biology, Faculdade de Medicina de Sao Jose do Rio Preto - FAMERP, Sao Jose do Rio Preto, SP, Brazil.
authors: Bruna Victorasso
authors: BV
authors: Jardim-Perassi
authors: Tumor angiogenesis laboratory, Cancer Center, Georgia Regents University, Augusta, GA, USA.
authors: A S M
authors: AS
authors: Iskander
authors: Cellular and Molecular Imaging Laboratory, Department of Radiology, Henry Ford Hospital, Detroit, MI, USA.
authors: Nadimpalli Ravi S
authors: NR
authors: Varma
authors: Tumor angiogenesis laboratory, Cancer Center, Georgia Regents University, Augusta, GA, USA.
authors: Adarsh
authors: A
authors: Shankar
authors: Laboratory of Molecular Investigation of Cancer - LIMC, Department of Molecular Biology, Faculdade de Medicina de Sao Jose do Rio Preto - FAMERP, Sao Jose do Rio Preto, SP, Brazil.
authors: Verena Benedick
authors: VB
authors: Coimbra
authors: Laboratory of Molecular Investigation of Cancer - LIMC, Department of Molecular Biology, Faculdade de Medicina de Sao Jose do Rio Preto - FAMERP, Sao Jose do Rio Preto, SP, Brazil.
authors: Vanessa Alves
authors: VA
authors: Fabri
authors: Universidade do Sagrado Coração (USC), Pro-Reitoria de Pesquisa e Pos-Graduação, Bauru, SP, Brazil.
authors: Juliana Garcia
authors: JG
authors: de Oliveira
authors: Laboratory of Molecular Investigation of Cancer - LIMC, Department of Molecular Biology, Faculdade de Medicina de Sao Jose do Rio Preto - FAMERP, Sao Jose do Rio Preto, SP, Brazil.|Universidade Estadual Paulista Julio de Mesquita Filho - IBILCE/UNESP, Sao Jose do Rio Preto, SP, Brazil.
authors: Debora Aparecida Pires de Campos
authors: DA
authors: Zuccari
mesh_terms: D000577:Amides / Q000494:pharmacology*; D000818:Animals; D001943:Breast Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D000072098:Single Photon Emission Computed Tomography Computed Tomography; D023041:Xenograft Model Antitumor Assays; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000577:Amides; D009363:Neoplasm Proteins; D011725:Pyridines; C108830:Y 27632; C515851:ROCK1 protein, human; D054460:rho-Associated Kinases; D008550:Melatonin
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