Resistance to senescence induction and telomere shortening by a G-quadruplex ligand inhibitor of telomerase.
The molecular mechanisms induced by G-quadruplex ligands to trigger senescence in mammalian cells are still unknown, although the critical role of telomerase is highly suspected. JFA2 cells selected for resistance to senescence induced by the G-quadruplex ligand 12459 presented an overexpression of hTERT transcript that correlated to a functional increase in telomerase activity and telomere length. Consistently, treatment with 12459 failed to trigger senescence and telomere shortening in JFA2 cells. Resistant cells also presented cross-resistance for senescence induction to telomestatin, another G-quadruplex ligand from a different series, but not to other anticancer agents, indicating the selectivity of the resistance mechanism. We, thus, provide evidence that telomerase activity and telomere length are key cellular determinants of the resistance to G-quadruplex ligands.
Gomez
Dennis
D
Onco-Pharmacologie, Unité Mixte de Recherche (UMR), 6142 Centre National de la Recherche Scientifique (CNRS), Unité de Formation et de Recherche de Pharmacie, Université de Reims Champagne-Ardenne, 51096 Reims Cedex, France.
Aouali
Nassera
N
Renaud
Alexandra
A
Douarre
Céline
C
Shin-Ya
Kazuo
K
Tazi
Jamal
J
Martinez
Sophie
S
Trentesaux
Chantal
C
Morjani
Hamid
H
Riou
Jean-François
JF
D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects / Q000502:physiology; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D054856:G-Quadruplexes; D006801:Humans; D008024:Ligands; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D016615:Telomere / Q000187:drug effects* / Q000502:physiology; D014227:Triazines / Q000494:pharmacology*
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D008024:Ligands; D012333:RNA, Messenger; D014227:Triazines; D004247:DNA; D019098:Telomerase