Sequence-specific targeting of IGF-I and IGF-IR genes by camptothecins
| Autor: | Géraldine Toutirais, Ludovic Halby, Catherine Senamaud-Beaufort, Jean-Christophe François, Paola B. Arimondo, Claudio Pisano, Kahina Oussedik, Sabrina Dallavalle, Yves Pommier |
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| Rok vydání: | 2010 |
| Předmět: |
DNA damage
Topoisomerase-I Inhibitor Biochemistry Cell Line Receptor IGF Type 1 Research Communications Growth factor receptor Gene expression Genetics medicine Animals Humans Enzyme Inhibitors Insulin-Like Growth Factor I Promoter Regions Genetic Molecular Biology Gene Binding Sites biology Base Sequence Oligonucleotide Topoisomerase Molecular biology Antineoplastic Agents Phytogenic Rats biology.protein Camptothecin Topoisomerase I Inhibitors Biotechnology medicine.drug DNA Damage |
| Zdroj: | FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 24(7) |
| ISSN: | 1530-6860 |
| Popis: | We and others have clearly demonstrated that a topoisomerase I (Top1) inhibitor, such as camptothecin (CPT), coupled to a triplex-forming oligonucleotide (TFO) through a suitable linker can be used to cause site-specific cleavage of the targeted DNA sequence in in vitro models. Here we evaluated whether these molecular tools induce sequence-specific DNA damage in a genome context. We targeted the insulin-like growth factor (IGF)-I axis and in particular promoter 1 of IGF-I and intron 2 of type 1 insulin-like growth factor receptor (IGF-IR) in cancer cells. The IGF axis molecules represent important targets for anticancer strategies, because of their central role in oncogenic maintenance and metastasis processes. We chemically attached 2 CPT derivatives to 2 TFOs. Both conjugates efficiently blocked gene expression in cells, reducing the quantity of mRNA transcribed by 70–80%, as measured by quantitative RT-PCR. We confirmed that the inhibitory mechanism of these TFO conjugates was mediated by Top1-induced cleavage through the use of RNA interference experiments and a camptothecin-resistant cell line. In addition, induction of phospho-H2AX foci supports the DNA-damaging activity of TFO-CPT conjugates at specific sites. The evaluated conjugates induce a specific DNA damage at the target gene mediated by Top1.—Oussedik, K., Francois, J.-C., Halby, L., Senamaud-Beaufort, C., Toutirais, G., Dallavalle, S., Pommier, Y., Pisano, C., Arimondo, P. B. Sequence-specific targeting of IGF-I and IGF-IR genes by camptothecins. |
| Databáze: | OpenAIRE |
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