Modulation of cell cycles and apoptosis by apicidin in estrogen receptor (ER)-positive and-negative human breast cancer cells.
The histone deacetylase (HDAC) inhibitor, apicidin, has been shown to suppress the growth of human breast cancer cells. In this article, we examined the ability of apicidin to inhibit the proliferation of human breast cancer cell lines. Cell cycle regulators and apoptotic cell death were determined using Western blot analysis and DAPI fluorescence staining, respectively. Apicidin treatment produced significant increases in acetylated H3 and H4 levels. In MCF-7 cells, the expression of ERalpha and ERbeta was decreased in a dose-dependent manner after apicidin treatment. However, ERbeta expression was not changed in MDA-MB-231 cells. Apicidin (300 nM) significantly induced expression of p21Waf1 and p27Kip1. Expression levels of cell cycle regulator proteins (cyclin D1/CDK 4 and cyclin E/CDK 2) were markedly decreased by apicidin in MCF-7 cells, but not in MDA-MB-231 cells. Cell cycle analysis indicated that apicidin increased the proportion of cells in the G1 phase and decreased the proportion of cells in the S phase in MCF-7 cells. Significantly, increase in sub-G1 populations was observed in MCF-7 cells by apicidin treatment. Apicidin treatment resulted in the induction of apoptotic cell death which was confirmed by DAPI staining. Additionally, apicidin significantly increased the bax/bcl-2 ratio in MCF-7 cells. These results suggest that apicidin inhibits proliferation of ER-positive MCF-7 breast cancer cells by altering the expression of cell cycle regulator proteins and inducing apoptotic cell death. These distinctive cell-specific effects of apicidin on the modulation of cell cycle arrest and apoptosis may be associated with ERalpha-mediated transcriptional regulation.
Im
Ji Young
JY
Laboratory of Molecular Toxicology, College of Pharmacy, Pusan National University, San 30, Jangjeon-dong, Geumjeong-gu, Busan 609-735, South Korea.
Park
Hyeyoung
H
Kang
Keon Wook
KW
Choi
Wahn Soo
WS
Kim
Hyung Sik
HS
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001943:Breast Neoplasms / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D016193:G1 Phase / Q000187:drug effects / Q000502:physiology; D006801:Humans; D010456:Peptides, Cyclic / Q000494:pharmacology* / Q000627:therapeutic use; D011960:Receptors, Estrogen / Q000187:drug effects* / Q000378:metabolism
D004791:Enzyme Inhibitors; D010456:Peptides, Cyclic; D011960:Receptors, Estrogen; C102351:apicidin