Sodium butyrate inhibits the self-renewal capacity of endometrial tumor side-population cells by inducing a DNA damage response

Kiyoko Kato, Aya Kuhara, Tomoko Yoneda, Takafumi Inoue, Tomoka Takao, Tatsuhiro Ohgami, Li Dan, Ayumi Kuboyama, Soshi Kusunoki, Satoru Takeda, Norio Wake

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

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 [12Val] KRAS (RK12V cells) anddetermined 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 γH2AX foci were increased by NaB treatment of both RK12V-SP cells and RK12V-NSP cells. The expression levels of γH2AX, 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.

Original languageEnglish
Pages (from-to)1430-1439
Number of pages10
JournalMolecular cancer therapeutics
Volume10
Issue number8
DOIs
Publication statusPublished - Aug 2011
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Sodium butyrate inhibits the self-renewal capacity of endometrial tumor side-population cells by inducing a DNA damage response'. Together they form a unique fingerprint.

  • Cite this

    Kato, K., Kuhara, A., Yoneda, T., Inoue, T., Takao, T., Ohgami, T., Dan, L., Kuboyama, A., Kusunoki, S., Takeda, S., & Wake, N. (2011). Sodium butyrate inhibits the self-renewal capacity of endometrial tumor side-population cells by inducing a DNA damage response. Molecular cancer therapeutics, 10(8), 1430-1439. https://doi.org/10.1158/1535-7163.MCT-10-1062