Cargando…
Effects of valproic acid on the cell cycle and apoptosis through acetylation of histone and tubulin in a scirrhous gastric cancer cell line
BACKGROUND: Management of peritoneal dissemination is the most critical problem in gastric cancer. This study was performed to investigate the inhibitory effects of valproic acid (VPA) on a highly peritoneal-seeding cell line of human scirrhous gastric cancer, OCUM-2MD3, and to explore the mechanism...
Autores principales: | , , , , , , , , , , , , , |
---|---|
Formato: | Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2010
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2994814/ https://www.ncbi.nlm.nih.gov/pubmed/21080974 http://dx.doi.org/10.1186/1756-9966-29-149 |
_version_ | 1782193003621777408 |
---|---|
author | Yagi, Yasumichi Fushida, Sachio Harada, Shinichi Kinoshita, Jun Makino, Isamu Oyama, Katsunobu Tajima, Hidehiro Fujita, Hideto Takamura, Hiroyuki Ninomiya, Itasu Fujimura, Takashi Ohta, Tetsuo Yashiro, Masakazu Hirakawa, Kosei |
author_facet | Yagi, Yasumichi Fushida, Sachio Harada, Shinichi Kinoshita, Jun Makino, Isamu Oyama, Katsunobu Tajima, Hidehiro Fujita, Hideto Takamura, Hiroyuki Ninomiya, Itasu Fujimura, Takashi Ohta, Tetsuo Yashiro, Masakazu Hirakawa, Kosei |
author_sort | Yagi, Yasumichi |
collection | PubMed |
description | BACKGROUND: Management of peritoneal dissemination is the most critical problem in gastric cancer. This study was performed to investigate the inhibitory effects of valproic acid (VPA) on a highly peritoneal-seeding cell line of human scirrhous gastric cancer, OCUM-2MD3, and to explore the mechanism and the potential of VPA. METHODS: The effects of VPA on the growth of OCUM-2MD3 cells were assessed by MTT assay. In addition, paclitaxel (PTX) was combined with VPA to evaluate their synergistic effects. HDAC1 and HDAC2 expression were evaluated by western blotting in OCUM-2MD3 cells and other gastric cancer cell lines (TMK-1, MKN-28). The acetylation status of histone H3 and α-tubulin after exposure to VPA were analyzed by western blotting. The activities of cell cycle regulatory proteins and apoptosis-modulating proteins were also examined by western blotting. The effects of VPA in vivo were evaluated in a xenograft model, and apoptotic activity was assessed by TUNEL assay. RESULTS: OCUM-2MD3 cells showed high levels of HDAC1 and HDAC2 expression compared with TMK-1 and MKN-28. The concentration of VPA required for significant inhibition of cell viability (P < 0.05) was 5 mM at 24 h and 0.5 mM at 48 h and 72 h. The inhibition of VPA with PTX showed dose-dependent and combinatorial effects. VPA increased acetyl-histone H3, acetyl-α-tubulin, and p21WAF1 levels accompanied by upregulation of p27, caspase 3, and caspase 9, and downregulation of bcl-2, cyclin D1, and survivin. In the xenograft model experiment, the mean tumor volume of the VPA-treated group was significantly reduced by 36.4%, compared with that of the control group at 4 weeks after treatment (P < 0.01). The apoptotic index was significantly higher in the VPA-treated group (42.3% ± 3.5%) than in the control group (7.7% ± 2.5%) (P < 0.001). CONCLUSIONS: VPA induced dynamic modulation of histone H3 and α-tubulin acetylation in relation with the anticancer effect and the enhancement of PTX in the OCUM-2MD3 cell line. Therefore, VPA in combination with PTX is expected to be a promising therapy for peritoneal dissemination of scirrhous gastric cancer. |
format | Text |
id | pubmed-2994814 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-29948142010-12-01 Effects of valproic acid on the cell cycle and apoptosis through acetylation of histone and tubulin in a scirrhous gastric cancer cell line Yagi, Yasumichi Fushida, Sachio Harada, Shinichi Kinoshita, Jun Makino, Isamu Oyama, Katsunobu Tajima, Hidehiro Fujita, Hideto Takamura, Hiroyuki Ninomiya, Itasu Fujimura, Takashi Ohta, Tetsuo Yashiro, Masakazu Hirakawa, Kosei J Exp Clin Cancer Res Research BACKGROUND: Management of peritoneal dissemination is the most critical problem in gastric cancer. This study was performed to investigate the inhibitory effects of valproic acid (VPA) on a highly peritoneal-seeding cell line of human scirrhous gastric cancer, OCUM-2MD3, and to explore the mechanism and the potential of VPA. METHODS: The effects of VPA on the growth of OCUM-2MD3 cells were assessed by MTT assay. In addition, paclitaxel (PTX) was combined with VPA to evaluate their synergistic effects. HDAC1 and HDAC2 expression were evaluated by western blotting in OCUM-2MD3 cells and other gastric cancer cell lines (TMK-1, MKN-28). The acetylation status of histone H3 and α-tubulin after exposure to VPA were analyzed by western blotting. The activities of cell cycle regulatory proteins and apoptosis-modulating proteins were also examined by western blotting. The effects of VPA in vivo were evaluated in a xenograft model, and apoptotic activity was assessed by TUNEL assay. RESULTS: OCUM-2MD3 cells showed high levels of HDAC1 and HDAC2 expression compared with TMK-1 and MKN-28. The concentration of VPA required for significant inhibition of cell viability (P < 0.05) was 5 mM at 24 h and 0.5 mM at 48 h and 72 h. The inhibition of VPA with PTX showed dose-dependent and combinatorial effects. VPA increased acetyl-histone H3, acetyl-α-tubulin, and p21WAF1 levels accompanied by upregulation of p27, caspase 3, and caspase 9, and downregulation of bcl-2, cyclin D1, and survivin. In the xenograft model experiment, the mean tumor volume of the VPA-treated group was significantly reduced by 36.4%, compared with that of the control group at 4 weeks after treatment (P < 0.01). The apoptotic index was significantly higher in the VPA-treated group (42.3% ± 3.5%) than in the control group (7.7% ± 2.5%) (P < 0.001). CONCLUSIONS: VPA induced dynamic modulation of histone H3 and α-tubulin acetylation in relation with the anticancer effect and the enhancement of PTX in the OCUM-2MD3 cell line. Therefore, VPA in combination with PTX is expected to be a promising therapy for peritoneal dissemination of scirrhous gastric cancer. BioMed Central 2010-11-17 /pmc/articles/PMC2994814/ /pubmed/21080974 http://dx.doi.org/10.1186/1756-9966-29-149 Text en Copyright ©2010 Yagi 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 Yagi, Yasumichi Fushida, Sachio Harada, Shinichi Kinoshita, Jun Makino, Isamu Oyama, Katsunobu Tajima, Hidehiro Fujita, Hideto Takamura, Hiroyuki Ninomiya, Itasu Fujimura, Takashi Ohta, Tetsuo Yashiro, Masakazu Hirakawa, Kosei Effects of valproic acid on the cell cycle and apoptosis through acetylation of histone and tubulin in a scirrhous gastric cancer cell line |
title | Effects of valproic acid on the cell cycle and apoptosis through acetylation of histone and tubulin in a scirrhous gastric cancer cell line |
title_full | Effects of valproic acid on the cell cycle and apoptosis through acetylation of histone and tubulin in a scirrhous gastric cancer cell line |
title_fullStr | Effects of valproic acid on the cell cycle and apoptosis through acetylation of histone and tubulin in a scirrhous gastric cancer cell line |
title_full_unstemmed | Effects of valproic acid on the cell cycle and apoptosis through acetylation of histone and tubulin in a scirrhous gastric cancer cell line |
title_short | Effects of valproic acid on the cell cycle and apoptosis through acetylation of histone and tubulin in a scirrhous gastric cancer cell line |
title_sort | effects of valproic acid on the cell cycle and apoptosis through acetylation of histone and tubulin in a scirrhous gastric cancer cell line |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2994814/ https://www.ncbi.nlm.nih.gov/pubmed/21080974 http://dx.doi.org/10.1186/1756-9966-29-149 |
work_keys_str_mv | AT yagiyasumichi effectsofvalproicacidonthecellcycleandapoptosisthroughacetylationofhistoneandtubulininascirrhousgastriccancercellline AT fushidasachio effectsofvalproicacidonthecellcycleandapoptosisthroughacetylationofhistoneandtubulininascirrhousgastriccancercellline AT haradashinichi effectsofvalproicacidonthecellcycleandapoptosisthroughacetylationofhistoneandtubulininascirrhousgastriccancercellline AT kinoshitajun effectsofvalproicacidonthecellcycleandapoptosisthroughacetylationofhistoneandtubulininascirrhousgastriccancercellline AT makinoisamu effectsofvalproicacidonthecellcycleandapoptosisthroughacetylationofhistoneandtubulininascirrhousgastriccancercellline AT oyamakatsunobu effectsofvalproicacidonthecellcycleandapoptosisthroughacetylationofhistoneandtubulininascirrhousgastriccancercellline AT tajimahidehiro effectsofvalproicacidonthecellcycleandapoptosisthroughacetylationofhistoneandtubulininascirrhousgastriccancercellline AT fujitahideto effectsofvalproicacidonthecellcycleandapoptosisthroughacetylationofhistoneandtubulininascirrhousgastriccancercellline AT takamurahiroyuki effectsofvalproicacidonthecellcycleandapoptosisthroughacetylationofhistoneandtubulininascirrhousgastriccancercellline AT ninomiyaitasu effectsofvalproicacidonthecellcycleandapoptosisthroughacetylationofhistoneandtubulininascirrhousgastriccancercellline AT fujimuratakashi effectsofvalproicacidonthecellcycleandapoptosisthroughacetylationofhistoneandtubulininascirrhousgastriccancercellline AT ohtatetsuo effectsofvalproicacidonthecellcycleandapoptosisthroughacetylationofhistoneandtubulininascirrhousgastriccancercellline AT yashiromasakazu effectsofvalproicacidonthecellcycleandapoptosisthroughacetylationofhistoneandtubulininascirrhousgastriccancercellline AT hirakawakosei effectsofvalproicacidonthecellcycleandapoptosisthroughacetylationofhistoneandtubulininascirrhousgastriccancercellline |