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Reduction of lung metastasis, cell invasion, and adhesion in mouse melanoma by statin-induced blockade of the Rho/Rho-associated coiled-coil-containing protein kinase pathway

BACKGROUND: Melanomas are highly malignant and have high metastatic potential; hence, there is a need for new therapeutic strategies to prevent cell metastasis. In the present study, we investigated whether statins inhibit tumor cell migration, invasion, adhesion, and metastasis in the B16BL6 mouse...

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Autores principales: Kidera, Yasuhiro, Tsubaki, Masanobu, Yamazoe, Yuzuru, Shoji, Kaori, Nakamura, Haruyuki, Ogaki, Mitsuhiko, Satou, Takao, Itoh, Tatsuki, Isozaki, Misako, Kaneko, Junichi, Tanimori, Yoshihiro, Yanae, Masashi, Nishida, Shozo
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2949822/
https://www.ncbi.nlm.nih.gov/pubmed/20843370
http://dx.doi.org/10.1186/1756-9966-29-127
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author Kidera, Yasuhiro
Tsubaki, Masanobu
Yamazoe, Yuzuru
Shoji, Kaori
Nakamura, Haruyuki
Ogaki, Mitsuhiko
Satou, Takao
Itoh, Tatsuki
Isozaki, Misako
Kaneko, Junichi
Tanimori, Yoshihiro
Yanae, Masashi
Nishida, Shozo
author_facet Kidera, Yasuhiro
Tsubaki, Masanobu
Yamazoe, Yuzuru
Shoji, Kaori
Nakamura, Haruyuki
Ogaki, Mitsuhiko
Satou, Takao
Itoh, Tatsuki
Isozaki, Misako
Kaneko, Junichi
Tanimori, Yoshihiro
Yanae, Masashi
Nishida, Shozo
author_sort Kidera, Yasuhiro
collection PubMed
description BACKGROUND: Melanomas are highly malignant and have high metastatic potential; hence, there is a need for new therapeutic strategies to prevent cell metastasis. In the present study, we investigated whether statins inhibit tumor cell migration, invasion, adhesion, and metastasis in the B16BL6 mouse melanoma cell line. METHODS: The cytotoxicity of statins toward the B16BL6 cells were evaluated using a cell viability assay. As an experimental model, B16BL6 cells were intravenously injected into C57BL/6 mice. Cell migration and invasion were assessed using Boyden chamber assays. Cell adhesion analysis was performed using type I collagen-, type IV collagen-, fibronectin-, and laminin-coated plates. The mRNA levels, enzyme activities and protein levels of matrix metalloproteinases (MMPs) were determined using RT-PCR, activity assay kits, and Western blot analysis, respectively; the mRNA and protein levels of vary late antigens (VLAs) were also determined. The effects of statins on signal transduction molecules were determined by western blot analyses. RESULTS: We found that statins significantly inhibited lung metastasis, cell migration, invasion, and adhesion at concentrations that did not have cytotoxic effects on B16BL6 cells. Statins also inhibited the mRNA expressions and enzymatic activities of matrix metalloproteinases (MMPs). Moreover, they suppressed the mRNA and protein expressions of integrin α(2), integrin α(4), and integrin α(5 )and decreased the membrane localization of Rho, and phosphorylated LIM kinase (LIMK) and myosin light chain (MLC). CONCLUSIONS: The results indicated that statins suppressed the Rho/Rho-associated coiled-coil-containing protein kinase (ROCK) pathways, thereby inhibiting B16BL6 cell migration, invasion, adhesion, and metastasis. Furthermore, they markedly inhibited clinically evident metastasis. Thus, these findings suggest that statins have potential clinical applications for the treatment of tumor cell metastasis.
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spelling pubmed-29498222010-10-06 Reduction of lung metastasis, cell invasion, and adhesion in mouse melanoma by statin-induced blockade of the Rho/Rho-associated coiled-coil-containing protein kinase pathway Kidera, Yasuhiro Tsubaki, Masanobu Yamazoe, Yuzuru Shoji, Kaori Nakamura, Haruyuki Ogaki, Mitsuhiko Satou, Takao Itoh, Tatsuki Isozaki, Misako Kaneko, Junichi Tanimori, Yoshihiro Yanae, Masashi Nishida, Shozo J Exp Clin Cancer Res Research BACKGROUND: Melanomas are highly malignant and have high metastatic potential; hence, there is a need for new therapeutic strategies to prevent cell metastasis. In the present study, we investigated whether statins inhibit tumor cell migration, invasion, adhesion, and metastasis in the B16BL6 mouse melanoma cell line. METHODS: The cytotoxicity of statins toward the B16BL6 cells were evaluated using a cell viability assay. As an experimental model, B16BL6 cells were intravenously injected into C57BL/6 mice. Cell migration and invasion were assessed using Boyden chamber assays. Cell adhesion analysis was performed using type I collagen-, type IV collagen-, fibronectin-, and laminin-coated plates. The mRNA levels, enzyme activities and protein levels of matrix metalloproteinases (MMPs) were determined using RT-PCR, activity assay kits, and Western blot analysis, respectively; the mRNA and protein levels of vary late antigens (VLAs) were also determined. The effects of statins on signal transduction molecules were determined by western blot analyses. RESULTS: We found that statins significantly inhibited lung metastasis, cell migration, invasion, and adhesion at concentrations that did not have cytotoxic effects on B16BL6 cells. Statins also inhibited the mRNA expressions and enzymatic activities of matrix metalloproteinases (MMPs). Moreover, they suppressed the mRNA and protein expressions of integrin α(2), integrin α(4), and integrin α(5 )and decreased the membrane localization of Rho, and phosphorylated LIM kinase (LIMK) and myosin light chain (MLC). CONCLUSIONS: The results indicated that statins suppressed the Rho/Rho-associated coiled-coil-containing protein kinase (ROCK) pathways, thereby inhibiting B16BL6 cell migration, invasion, adhesion, and metastasis. Furthermore, they markedly inhibited clinically evident metastasis. Thus, these findings suggest that statins have potential clinical applications for the treatment of tumor cell metastasis. BioMed Central 2010-09-16 /pmc/articles/PMC2949822/ /pubmed/20843370 http://dx.doi.org/10.1186/1756-9966-29-127 Text en Copyright ©2010 Kidera et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research
Kidera, Yasuhiro
Tsubaki, Masanobu
Yamazoe, Yuzuru
Shoji, Kaori
Nakamura, Haruyuki
Ogaki, Mitsuhiko
Satou, Takao
Itoh, Tatsuki
Isozaki, Misako
Kaneko, Junichi
Tanimori, Yoshihiro
Yanae, Masashi
Nishida, Shozo
Reduction of lung metastasis, cell invasion, and adhesion in mouse melanoma by statin-induced blockade of the Rho/Rho-associated coiled-coil-containing protein kinase pathway
title Reduction of lung metastasis, cell invasion, and adhesion in mouse melanoma by statin-induced blockade of the Rho/Rho-associated coiled-coil-containing protein kinase pathway
title_full Reduction of lung metastasis, cell invasion, and adhesion in mouse melanoma by statin-induced blockade of the Rho/Rho-associated coiled-coil-containing protein kinase pathway
title_fullStr Reduction of lung metastasis, cell invasion, and adhesion in mouse melanoma by statin-induced blockade of the Rho/Rho-associated coiled-coil-containing protein kinase pathway
title_full_unstemmed Reduction of lung metastasis, cell invasion, and adhesion in mouse melanoma by statin-induced blockade of the Rho/Rho-associated coiled-coil-containing protein kinase pathway
title_short Reduction of lung metastasis, cell invasion, and adhesion in mouse melanoma by statin-induced blockade of the Rho/Rho-associated coiled-coil-containing protein kinase pathway
title_sort reduction of lung metastasis, cell invasion, and adhesion in mouse melanoma by statin-induced blockade of the rho/rho-associated coiled-coil-containing protein kinase pathway
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2949822/
https://www.ncbi.nlm.nih.gov/pubmed/20843370
http://dx.doi.org/10.1186/1756-9966-29-127
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