Valproic acid inhibits proliferation of HER2-expressing breast cancer cells by inducing cell cycle arrest and apoptosis through Hsp70 acetylation
| Autor: | Katsunobu Oyama, Tetsuo Ohta, Toshiki Mawatari, Itasu Ninomiya, Sachio Fushida, Shinichi Harada, Isamu Makino, Hisatoshi Nakagawara, Hiroyuki Takamura, Tomoharu Miyashita, Hidehiro Tajima, Hironori Hayashi, Masafumi Inokuchi |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Cancer Research
Cell cycle checkpoint Receptor ErbB-2 Cell Blotting Western Hsp90 Apoptosis Breast Neoplasms Biology Hsp70 breast cancer HDAC inhibitor HER2 Cell Line Tumor medicine In Situ Nick-End Labeling Humans Immunoprecipitation HSP70 Heat-Shock Proteins HSP90 Heat-Shock Proteins skin and connective tissue diseases Cell Proliferation Cell growth Valproic Acid Cancer Acetylation Articles Cell Cycle Checkpoints Cell cycle medicine.disease Immunohistochemistry Histone Deacetylase Inhibitors medicine.anatomical_structure Oncology SKBR3 Drug Resistance Neoplasm Cancer research lipids (amino acids peptides and proteins) Female Histone deacetylase |
| Zdroj: | International Journal of Oncology |
| ISSN: | 1791-2423 1019-6439 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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