Telomere dysfunction alters the chemotherapeutic profile of transformed cells

Kee Ho Lee, K. Lenhard Rudolph, Yeun Jin Ju, Roger A. Greenberg, Linda Cannizzaro, Lynda Chin, Sarah R. Weiler, Ronald A. DePinho

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Abstract

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 doublestranded 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.

Original languageEnglish (US)
Pages (from-to)3381-3386
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number6
DOIs
Publication statusPublished - Mar 13 2001

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Lee, K. H., Rudolph, K. L., Ju, Y. J., Greenberg, R. A., Cannizzaro, L., Chin, L., ... DePinho, R. A. (2001). Telomere dysfunction alters the chemotherapeutic profile of transformed cells. Proceedings of the National Academy of Sciences of the United States of America, 98(6), 3381-3386. https://doi.org/10.1073/pnas.051629198