Inhibition of Ataxia Telangiectasia- and Rad3 -Related Function Abrogates the In Vitro and In Vivo Tumorigenicity of Human Colon Cancer Cells Through Depletion of the CD133+ Tumor-Initiating Cell Fraction

Stem Cells - Tập 29 Số 3 - Trang 418-429 - 2011
Eike Gallmeier1, Patrick Hermann2, M Mueller2, Juan G. Machado2, Andreas Ziesch1, Enrico N. De Toni1, Andreas Palagyi1, Christian Eisen3, Joachim W. Ellwart4, José Rivera2, Belén Rubio‐Viqueira2, Manuel Hidalgo2, Fred Bunz5, Burkhard Göke1, Christopher Heeschen2
1Department of Medicine II, Campus Grosshadern, Ludwigs-Maximilian-University of Munich, Munich, Germany
2Clinical Research Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
3Division of Stem Cells and Cancer, German Cancer Research Centre (DKFZ), Heidelberg, Germany
4Institute of Molecular Immunology, Helmholtz Centre, Munich, Germany
5Department of Radiation Oncology at Johns Hopkins University, Baltimore, Maryland, USA

Tóm tắt

AbstractThe identification of novel approaches to specifically target the DNA-damage checkpoint response in chemotherapy-resistant cancer stem cells (CSC) of solid tumors has recently attracted great interest. We show here in colon cancer cell lines and primary colon cancer cells that inhibition of checkpoint-modulating phosphoinositide 3-kinase-related (PIK) kinases preferentially depletes the chemoresistant and exclusively tumorigenic CD133+ cell fraction. We observed a time- and dose-dependent disproportionally pronounced loss of CD133+ cells and the consecutive lack of in vitro and in vivo tumorigenicity of the remaining cells. Depletion of CD133+ cells was initiated through apoptosis of cycling CD133+ cells and further substantiated through subsequent recruitment of quiescent CD133+ cells into the cell cycle followed by their elimination. Models using specific PIK kinase inhibitors, somatic cell gene targeting, and RNA interference demonstrated that the observed detrimental effects of caffeine on CSC were attributable specifically to the inhibition of the PIK kinase ataxia telangiectasia- and Rad3-related (ATR). Mechanistically, phosphorylation of CHK1 checkpoint homolog (S. pombe; CHK1) was significantly enhanced in CD133+ as compared with CD133− cells on treatment with DNA interstrand-crosslinking (ICL) agents, indicating a preferential activation of the ATR/CHK1-dependent DNA-damage response in tumorigenic CD133+ cells. Consistently, the chemoresistance of CD133+ cells toward DNA ICL agents was overcome through inhibition of ATR/CHK1-signaling. In conclusion, our study illustrates a novel target to eliminate the tumorigenic CD133+ cell population in colon cancer and provides another rationale for the development of specific ATR-inhibitors.

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Stem Cells

Tập 29 Số 3

418-429

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