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

19 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 1 2011

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Side-Population Cells
Butyric Acid
DNA Damage
Neoplastic Stem Cells
Neoplasms
Histone Deacetylases
Endometrial Neoplasms
Reactive Oxygen Species
Cell Line
Differentiation Antigens
p38 Mitogen-Activated Protein Kinases
Stromal Cells
Population
Agar

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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Sodium butyrate inhibits the self-renewal capacity of endometrial tumor side-population cells by inducing a DNA damage response. / Kato, Kiyoko; Kuhara, Aya; Yoneda, Tomoko; Inoue, Takafumi; Takao, Tomoka; Ohgami, Tatsuhiro; Dan, Li; Kuboyama, Ayumi; Kusunoki, Soshi; Takeda, Satoru; Wake, Norio.

In: Molecular Cancer Therapeutics, Vol. 10, No. 8, 01.08.2011, p. 1430-1439.

Research output: Contribution to journalArticle

Kato, Kiyoko ; Kuhara, Aya ; Yoneda, Tomoko ; Inoue, Takafumi ; Takao, Tomoka ; Ohgami, Tatsuhiro ; Dan, Li ; Kuboyama, Ayumi ; Kusunoki, Soshi ; Takeda, Satoru ; Wake, Norio. / Sodium butyrate inhibits the self-renewal capacity of endometrial tumor side-population cells by inducing a DNA damage response. In: Molecular Cancer Therapeutics. 2011 ; Vol. 10, No. 8. pp. 1430-1439.
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AU - Ohgami, Tatsuhiro

AU - Dan, Li

AU - Kuboyama, Ayumi

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AU - Takeda, Satoru

AU - Wake, Norio

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