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Effects of apicidin, a histone deacetylase inhibitor, on the regulation of apoptosis in H-ras-transformed breast epithelial cells.
- Source :
-
International journal of molecular medicine [Int J Mol Med] 2008 Mar; Vol. 21 (3), pp. 325-33. - Publication Year :
- 2008
-
Abstract
- The cellular susceptibility of cancer cells to histone deacetylase (HDAC) inhibitors is increased by the etopic expression of oncogenic Ras. However, the ability of HDAC inhibitors to regulate the apoptotic pathway in human breast cancer cells is still not completely understood. In this study, the anti-proliferative effects of apicidin were compared in H-ras-transformed human breast epithelial (MCF10A-ras) and non-transformed epithelial (MCF10A) cells. MCF10A-ras cells showed a significantly higher growth rate than MCF10A cells. Apicidin significantly increased the levels of acetylated histone H3 and H4 in both cell lines. Western blot analysis and flow cytometry were used to determine if the anti-proliferative effects of apicidin in MCF10A and MCF10A-ras cells could be mediated by modulating the cell cycle. Apicidin attenuated the expression of cyclin E and CDK2 in MCF10A cells, decreased cyclin D1 and cyclin E levels in MCF10A-ras cells, and increased the levels of CDK inhibitors, p21WAF1/Cip1 and p27Kip1, in both cell lines. Notably, the levels of hyperphosphorylation of the Rb protein levels were lower in the MCF10A-ras cells after apicidin treatment. Studies on the regulation of apoptosis showed that apicidin induces the up-regulation of p53 and the downstream activation of ERK in MCF10A-ras cells. The up-regulation of p53 promoted Bax expression leading to activation of caspases-9 and -6, and eventually to apoptosis in MCF10A-ras cells. In addition, apicidin significantly increased the levels of ERK1/2 phosphorylation in MCF10A-ras cells. Therefore, the apicidin-mediated ERK pathway appears to play an important role in modulating the pro-apoptotic pathway in MCF10A-ras cells.
- Subjects :
- Acetylation drug effects
Breast drug effects
Breast enzymology
Cell Cycle drug effects
Cell Cycle Proteins metabolism
Cell Line, Tumor
Cell Transformation, Neoplastic drug effects
Enzyme Activation drug effects
Epithelial Cells drug effects
Epithelial Cells enzymology
Female
Histones metabolism
Humans
Mitogen-Activated Protein Kinase 1 metabolism
Mitogen-Activated Protein Kinase 3 metabolism
Peptides, Cyclic chemistry
Transcription Factor AP-1 metabolism
Transfection
Apoptosis drug effects
Breast pathology
Enzyme Inhibitors pharmacology
Epithelial Cells pathology
Histone Deacetylase Inhibitors
Peptides, Cyclic pharmacology
Proto-Oncogene Proteins p21(ras) metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1107-3756
- Volume :
- 21
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- International journal of molecular medicine
- Publication Type :
- Academic Journal
- Accession number :
- 18288380