期刊
MOLECULAR CANCER THERAPEUTICS
卷 10, 期 8, 页码 1430-1439出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-10-1062
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资金
- Ministry of Education, Culture, Sports, Science and Technology, Japan [20659259, 22659302, 22591869]
- Ministry of the Environment, Japan
- Grants-in-Aid for Scientific Research [22659302, 20659259, 22591869] Funding Source: KAKEN
We previously isolated side-population (SP) cells from a human endometrial cancer cell line, Hec1, and determined that Hec1-SP cells have cancer stem-like cell features. In this study, we isolated SP cells and non-SP (NSP) cells derived from a rat endometrial cell line expressing human [(12)Val] KRAS (RK12V cells) and determined the SP phenotype. RK12V-SP cells showed self-renewal capacity, the potential to develop into stromal cells, reduced expression levels of differentiation markers, long-term proliferating capacity in cultures, and enhanced tumorigenicity, indicating that RK12V-SP cells have cancer stem-like cell features. RK12V-SP cells also display higher resistance to conventional chemotherapeutic drugs. In contrast, treatment with a histone deacetylases (HDAC) inhibitor, sodium butyrate (NaB), reduced self-renewal capacity and completely suppressed colony formation of RK12V-SP cells in a soft agar. The levels of intracellular reactive oxygen species (ROS) and the number of gamma H2AX foci were increased by NaB treatment of both RK12V-SP cells and RK12V-NSP cells. The expression levels of gamma H2AX, p21, p27, and phospho-p38 mitogen-activated protein kinase were enhanced in RK12V-SP cells compared with RK12V-NSP cells. These results imply that treatment with NaB induced production of intracellular ROS and DNA damage in both RK12V-SP and RK12V-NSP cells. Following NaB treatment, DNA damage response signals were enhanced more in RK12V-SP cells than in RK12V-NSP cells. This is the first article on an inhibitory effect of NaB on proliferation of endometrial cancer stem-like cells. HDAC inhibitors may represent an attractive antitumor therapy based upon their inhibitory effects on cancer stem-like cells. Mol Cancer Ther; 10(8); 1430-9. (C) 2011 AACR.
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