Resistance to the Short Term Antiproliferative Activity of the G-quadruplex Ligand 12459 Is Associated with Telomerase Overexpression and Telomere Capping Alteration

Dennis Gomez, Nassera Aouali, Arturo Londoño-Vallejo, Laurent Lacroix, Frédérique Mégnin-Chanet, Thibault Lemarteleur, Céline Douarre, Kazuo Shin-Ya, Patriek Mailliet, Chantal Trentesaux, Hamid Morjani, Jean Louis Mergny, Jean François Riou*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

57 Citations (Scopus)

Abstract

Ligands that stabilize the telomeric G-rich single-stranded DNA overhang into G-quadruplex can be considered as potential antitumor agents that block telomere replication. Ligand 12459, a potent G-quadruplex ligand that belongs to the triazine series, has been previously shown to induce both telomere shortening and apoptosis in the human A549 cell line as a function of its concentration and time exposure. We show here that A549 clones obtained after mutagenesis and selected for resistance to the short term effect of ligand 12459 frequently displayed hTERT transcript overexpression (2-6-fold). Overexpression of hTERT was also characterized in two resistant clones (JFD10 and JFD18) as an increase in telomerase activity, leading to an increase in telomere length. An increased frequency of anaphase bridges was also detected in JFD10 and JFD18, suggesting an alteration of telomere capping functions. Transfection of either hTERT or DN-hTERT cDNAs into A549 cells did not confer resistance or hypersensitivity to the short term effect of ligand 12459, indicating that telomerase expression is not the main determinant of the antiproliferative effect of ligand 12459. In contrast, transfection of DN-hTERT cDNA into resistant JFD18 cells restored sensitivity to apoptotic concentrations of ligand 12459, suggesting that telomerase does participate in the resistance to this G-quadruplex ligand. This work provides evidence that telomerase activity is not the main target for the 12459 G-quadruplex ligand but that hTERT functions contribute to the resistance phenotype to this class of agents.

Original languageEnglish
Pages (from-to)50554-50562
Number of pages9
JournalJournal of Biological Chemistry
Volume278
Issue number50
DOIs
Publication statusPublished - 12 Dec 2003
Externally publishedYes

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