Telomere dysfunction alters the chemotherapeutic profile of transformed cells.
Telomerase inhibition has been touted as a novel cancer-selective therapeutic goal based on the observation of high telomerase levels in most cancers and the importance of telomere maintenance in long-term cellular growth and survival. Here, the impact of telomere dysfunction on chemotherapeutic responses was assessed in normal and neoplastic cells derived from telomerase RNA null (mTERC(-/-)) mice. Telomere dysfunction, rather than telomerase per se, was found to be the principal determinant governing chemosensitivity specifically to agents that induced double-stranded DNA breaks (DSB). Enhanced chemosensitivity in telomere dysfunctional cells was linked to therapy-induced fragmentation and multichromosomal fusions, whereas telomerase reconstitution restored genomic integrity and chemoresistance. Loss of p53 function muted the cytotoxic effects of DSB-inducing agents in cells with telomere dysfunction. Together, these results point to the combined use of DSB-inducing agents and telomere maintenance inhibition as an effective anticancer therapeutic approach particularly in cells with intact p53-dependent checkpoint responses.
Lee
K H
KH
Department of Adult Oncology, Dana-Farber Cancer Institute, Departments of Medicine and Genetics, and Dermatology, Harvard Medical School, Boston, MA 02115, USA.
Rudolph
K L
KL
Ju
Y J
YJ
Greenberg
R A
RA
Cannizzaro
L
L
Chin
L
L
Weiler
S R
SR
DePinho
R A
RA
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002461:Cell Line, Transformed; D002945:Cisplatin / Q000494:pharmacology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000502:physiology; D004317:Doxorubicin / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D012313:RNA / Q000235:genetics / Q000502:physiology*; D019098:Telomerase / Q000235:genetics / Q000502:physiology*; D016615:Telomere / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology; D018631:ras Proteins / Q000235:genetics
D000970:Antineoplastic Agents; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; C422952:telomerase RNA; D012313:RNA; D005047:Etoposide; D004317:Doxorubicin; D019098:Telomerase; D018631:ras Proteins; D002945:Cisplatin; D005472:Fluorouracil