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
| العنوان: | 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 |
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| المؤلفون: | Maria-Theresa Mueller, Fred Bunz, Juan G. Machado, Eike Gallmeier, Joachim W. Ellwart, Enrico N. De Toni, Christian Eisen, Christopher Heeschen, Belen Rubio-Viqueira, Andreas Ziesch, Burkhard Göke, Manuel Hidalgo, Jose Rivera, Patrick C. Hermann, Andreas Palagyi |
| المصدر: | STEM CELLS STEM CELLS; Vol 29 Stem Cells 29, 418-429 (2011) |
| بيانات النشر: | Oxford University Press (OUP), 2011. |
| سنة النشر: | 2011 |
| مصطلحات موضوعية: | Somatic cell, Cell, Cell Cycle Proteins, Ataxia Telangiectasia Mutated Proteins, Cell Separation, Mice, 0302 clinical medicine, AC133 Antigen, Molecular Targeted Therapy, RNA, Small Interfering, 0303 health sciences, Kinase, Cell cycle, 3. Good health, Gene Expression Regulation, Neoplastic, Cell Transformation, Neoplastic, medicine.anatomical_structure, Biochemistry, 030220 oncology & carcinogenesis, Colonic Neoplasms, embryonic structures, Neoplastic Stem Cells, Molecular Medicine, Female, biological phenomena, cell phenomena, and immunity, Down-Regulation, Mice, Nude, ATR, Cancer stem cells, Colon cancer, DNA-damage response, Tumor-initiating cells, Protein Serine-Threonine Kinases, Biology, 03 medical and health sciences, Antigens, CD, Cancer stem cell, Cell Line, Tumor, medicine, Animals, Humans, Glycoproteins, 030304 developmental biology, Carcinoma, Genetic Therapy, Cell Biology, medicine.disease, Xenograft Model Antitumor Assays, Cell culture, Ataxia-telangiectasia, Cancer research, Peptides, Ataxia telangiectasia and Rad3 related, Developmental Biology |
| الوصف: | 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 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. |
| وصف الملف: | application/pdf |
| تدمد: | 1549-4918 1066-5099 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::295e835de87b558e6cdbd2dd4774700fTest https://doi.org/10.1002/stem.595Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....295e835de87b558e6cdbd2dd4774700f |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15494918 10665099 |
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