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Valproic acid inhibits proliferation of HER2-expressing breast cancer cells by inducing cell cycle arrest and apoptosis through Hsp70 acetylation

Breast cancer encompasses a heterogeneous group of diseases at the molecular level. It is known that chemo-sensitivity of breast cancer depends on its molecular subtype. We investigated the growth inhibitory effect of valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, and the mechanism of...

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Autores principales: MAWATARI, TOSHIKI, NINOMIYA, ITASU, INOKUCHI, MASAFUMI, HARADA, SHINICHI, HAYASHI, HIRONORI, OYAMA, KATSUNOBU, MAKINO, ISAMU, NAKAGAWARA, HISATOSHI, MIYASHITA, TOMOHARU, TAJIMA, HIDEHIRO, TAKAMURA, HIROYUKI, FUSHIDA, SACHIO, OHTA, TETSUO
Formato: Online Artículo Texto
Lenguaje:English
Publicado: D.A. Spandidos 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4665753/
https://www.ncbi.nlm.nih.gov/pubmed/26497673
http://dx.doi.org/10.3892/ijo.2015.3213
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author MAWATARI, TOSHIKI
NINOMIYA, ITASU
INOKUCHI, MASAFUMI
HARADA, SHINICHI
HAYASHI, HIRONORI
OYAMA, KATSUNOBU
MAKINO, ISAMU
NAKAGAWARA, HISATOSHI
MIYASHITA, TOMOHARU
TAJIMA, HIDEHIRO
TAKAMURA, HIROYUKI
FUSHIDA, SACHIO
OHTA, TETSUO
author_facet MAWATARI, TOSHIKI
NINOMIYA, ITASU
INOKUCHI, MASAFUMI
HARADA, SHINICHI
HAYASHI, HIRONORI
OYAMA, KATSUNOBU
MAKINO, ISAMU
NAKAGAWARA, HISATOSHI
MIYASHITA, TOMOHARU
TAJIMA, HIDEHIRO
TAKAMURA, HIROYUKI
FUSHIDA, SACHIO
OHTA, TETSUO
author_sort MAWATARI, TOSHIKI
collection PubMed
description Breast cancer encompasses a heterogeneous group of diseases at the molecular level. It is known that chemo-sensitivity of breast cancer depends on its molecular subtype. We investigated the growth inhibitory effect of valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, and the mechanism of this inhibition on four breast cancer cell lines with different molecular subtypes. The growth inhibitory effect of VPA in the four different breast cancer cell lines was investigated. The alteration of levels of p21 WAF1, cleaved caspase-3, acetylated Heat shock protein (Hsp) 90, acetylated Hsp70, and acetylated α-tubulin by VPA was examined in VPA-sensitive, human epidermal receptor 2 (HER2)-overexpressing SKBR3 cells. The cell growth inhibition of breast cancer cell lines was dependent on the dose and exposure time of VPA. The cell growth of HER2-overexpressing SKBR3 cell line was inhibited by VPA to a much greater degree than other cell lines studied. In SKBR3 cell line, VPA upregulated expression of p21 WAF1 and cleaved caspase-3 in the early phase. VPA markedly increased Hsp70 acetylation in a time-dependent manner but did not increase Hsp90 acetylation. Our data demonstrated that VPA inhibited cell proliferation and induced cell cycle arrest and apoptosis of HER2-overexpressing breast cancer cells. This anti-proliferation effect might be the direct function of VPA as an HDAC inhibitor. We propose an alternative mechanism whereby acetylation of Hsp70 disrupts the function of Hsp90 and leads to downregulation of its client proteins, including HER2 that might be the indirect function of VPA, in the sense that non-histone proteins are acetylated.
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spelling pubmed-46657532015-12-04 Valproic acid inhibits proliferation of HER2-expressing breast cancer cells by inducing cell cycle arrest and apoptosis through Hsp70 acetylation MAWATARI, TOSHIKI NINOMIYA, ITASU INOKUCHI, MASAFUMI HARADA, SHINICHI HAYASHI, HIRONORI OYAMA, KATSUNOBU MAKINO, ISAMU NAKAGAWARA, HISATOSHI MIYASHITA, TOMOHARU TAJIMA, HIDEHIRO TAKAMURA, HIROYUKI FUSHIDA, SACHIO OHTA, TETSUO Int J Oncol Articles Breast cancer encompasses a heterogeneous group of diseases at the molecular level. It is known that chemo-sensitivity of breast cancer depends on its molecular subtype. We investigated the growth inhibitory effect of valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, and the mechanism of this inhibition on four breast cancer cell lines with different molecular subtypes. The growth inhibitory effect of VPA in the four different breast cancer cell lines was investigated. The alteration of levels of p21 WAF1, cleaved caspase-3, acetylated Heat shock protein (Hsp) 90, acetylated Hsp70, and acetylated α-tubulin by VPA was examined in VPA-sensitive, human epidermal receptor 2 (HER2)-overexpressing SKBR3 cells. The cell growth inhibition of breast cancer cell lines was dependent on the dose and exposure time of VPA. The cell growth of HER2-overexpressing SKBR3 cell line was inhibited by VPA to a much greater degree than other cell lines studied. In SKBR3 cell line, VPA upregulated expression of p21 WAF1 and cleaved caspase-3 in the early phase. VPA markedly increased Hsp70 acetylation in a time-dependent manner but did not increase Hsp90 acetylation. Our data demonstrated that VPA inhibited cell proliferation and induced cell cycle arrest and apoptosis of HER2-overexpressing breast cancer cells. This anti-proliferation effect might be the direct function of VPA as an HDAC inhibitor. We propose an alternative mechanism whereby acetylation of Hsp70 disrupts the function of Hsp90 and leads to downregulation of its client proteins, including HER2 that might be the indirect function of VPA, in the sense that non-histone proteins are acetylated. D.A. Spandidos 2015-10-20 /pmc/articles/PMC4665753/ /pubmed/26497673 http://dx.doi.org/10.3892/ijo.2015.3213 Text en Copyright: © Mawatari et al. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
spellingShingle Articles
MAWATARI, TOSHIKI
NINOMIYA, ITASU
INOKUCHI, MASAFUMI
HARADA, SHINICHI
HAYASHI, HIRONORI
OYAMA, KATSUNOBU
MAKINO, ISAMU
NAKAGAWARA, HISATOSHI
MIYASHITA, TOMOHARU
TAJIMA, HIDEHIRO
TAKAMURA, HIROYUKI
FUSHIDA, SACHIO
OHTA, TETSUO
Valproic acid inhibits proliferation of HER2-expressing breast cancer cells by inducing cell cycle arrest and apoptosis through Hsp70 acetylation
title Valproic acid inhibits proliferation of HER2-expressing breast cancer cells by inducing cell cycle arrest and apoptosis through Hsp70 acetylation
title_full Valproic acid inhibits proliferation of HER2-expressing breast cancer cells by inducing cell cycle arrest and apoptosis through Hsp70 acetylation
title_fullStr Valproic acid inhibits proliferation of HER2-expressing breast cancer cells by inducing cell cycle arrest and apoptosis through Hsp70 acetylation
title_full_unstemmed Valproic acid inhibits proliferation of HER2-expressing breast cancer cells by inducing cell cycle arrest and apoptosis through Hsp70 acetylation
title_short Valproic acid inhibits proliferation of HER2-expressing breast cancer cells by inducing cell cycle arrest and apoptosis through Hsp70 acetylation
title_sort valproic acid inhibits proliferation of her2-expressing breast cancer cells by inducing cell cycle arrest and apoptosis through hsp70 acetylation
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4665753/
https://www.ncbi.nlm.nih.gov/pubmed/26497673
http://dx.doi.org/10.3892/ijo.2015.3213
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