title: Resistance to the short term antiproliferative activity of the G-quadruplex ligand 12459 is associated with telomerase overexpression and telomere capping alteration.
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.
authors.affiliation: Onco-Pharmacologie, IFR53, UFR de Pharmacie, Université de Reims Champagne-Ardenne, Reims 51096, France.
authors.forename: Dennis
authors.initials: D
authors.lastname: Gomez
authors.forename: Nassera
authors.initials: N
authors.lastname: Aouali
authors.forename: Arturo
authors.initials: A
authors.lastname: Londoño-Vallejo
authors.forename: Laurent
authors.initials: L
authors.lastname: Lacroix
authors.forename: Frédérique
authors.initials: F
authors.lastname: Mégnin-Chanet
authors.forename: Thibault
authors.initials: T
authors.lastname: Lemarteleur
authors.forename: Céline
authors.initials: C
authors.lastname: Douarre
authors.forename: Kazuo
authors.initials: K
authors.lastname: Shin-ya
authors.forename: Patrick
authors.initials: P
authors.lastname: Mailliet
authors.forename: Chantal
authors.initials: C
authors.lastname: Trentesaux
authors.forename: Hamid
authors.initials: H
authors.lastname: Morjani
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Mergny
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Riou
mesh_terms: D002455:Cell Division; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D018432:Drug Resistance, Multiple; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D020128:Inhibitory Concentration 50; D008024:Ligands; D009154:Mutation; D009841:Oligonucleotides / Q000378:metabolism; D010641:Phenotype; D011485:Protein Binding; D011806:Quinolinium Compounds / Q000737:chemistry* / Q000494:pharmacology; D012313:RNA / Q000378:metabolism; D011839:Radiation, Ionizing; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019098:Telomerase / Q000096:biosynthesis* / Q000378:metabolism; D016615:Telomere / Q000378:metabolism / Q000648:ultrastructure*; D014162:Transfection; D014227:Triazines / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C480235:G-quadruplex ligand 12459; D008024:Ligands; D009841:Oligonucleotides; D011806:Quinolinium Compounds; D014227:Triazines; D012313:RNA; D004247:DNA; D019098:Telomerase