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

作者：Eike Gallmeier, Patrick Hermann, M Mueller, Juan G. Machado, Andreas Ziesch, Enrico N. De Toni, Andreas Palagyi, Christian Eisen, Joachim W. Ellwart, José Rivera, Belén Rubio‐Viqueira, Manuel Hidalgo, Fred Bunz, Burkhard Göke, Christopher Heeschen · 发表于：Stem Cells · 年份：2011 · DOI：10.1002/stem.595 · 被引用次数：105 · 研究领域：Cancer Cells and Metastasis、DNA Repair Mechanisms、Cancer-related Molecular Pathways

The 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 CD1...