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Overexpression of Bcl-2 is associated with apoptotic resistance to the G-quadruplex ligand 12459 but is not sufficient to confer resistance to long-term senescence.

Abstract : The triazine derivative 12459 is a potent G-quadruplex interacting agent that inhibits telomerase activity. This agent induces time- and dose-dependent telomere shortening, senescence-like growth arrest and apoptosis in the human A549 tumour cell line. We show here that 12459 induces a delayed apoptosis that activates the mitochondrial pathway. A549 cell lines selected for resistance to 12459 and previously characterized for an altered hTERT expression also showed Bcl-2 overexpression. Transfection of Bcl-2 into A549 cells induced a resistance to the short-term apoptotic effect triggered by 12459, suggesting that Bcl-2 is an important determinant for the activity of 12459. In sharp contrast, the Bcl-2 overexpression was not sufficient to confer resistance to the senescence-like growth arrest induced by prolonged treatment with 12459. We also show that 12459 provokes a rapid degradation of the telomeric G-overhang in conditions that paralleled the apoptosis induction. In contrast, the G-overhang degradation was not observed when apoptosis was induced by camptothecin. Bcl-2 overexpression did not modify the G-overhang degradation, suggesting that this event is an early process uncoupled from the final apoptotic pathway.
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https://www.hal.inserm.fr/inserm-00145639
Contributor : Philippe Birembaut <>
Submitted on : Wednesday, September 17, 2008 - 10:18:59 AM
Last modification on : Wednesday, October 23, 2019 - 10:16:02 AM
Long-term archiving on: : Wednesday, April 7, 2010 - 1:21:05 AM

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Céline Douarre, Dennis Gomez, Hamid Morjani, Jean-Marie Zahm, Marie-Françoise O'Donohue, et al.. Overexpression of Bcl-2 is associated with apoptotic resistance to the G-quadruplex ligand 12459 but is not sufficient to confer resistance to long-term senescence.. Nucleic Acids Research, Oxford University Press, 2005, 33 (7), pp.2192-203. ⟨10.1093/nar/gki514⟩. ⟨inserm-00145639⟩

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