Resistance to the short term antiproliferative activity of the G-quadruplex ligand 12459 is associated with telomerase overexpression and telomere capping alteration.
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.
Gomez
Dennis
D
Onco-Pharmacologie, IFR53, UFR de Pharmacie, Université de Reims Champagne-Ardenne, Reims 51096, France.
Aouali
Nassera
N
Londoño-Vallejo
Arturo
A
Lacroix
Laurent
L
Mégnin-Chanet
Frédérique
F
Lemarteleur
Thibault
T
Douarre
Céline
C
Shin-ya
Kazuo
K
Mailliet
Patrick
P
Trentesaux
Chantal
C
Morjani
Hamid
H
Mergny
Jean-Louis
JL
Riou
Jean-François
JF
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
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