High-Throughput RNAi Screening Reveals Novel Regulators of Telomerase

Telomerase is considered an attractive anticancer target on the basis of its common and specific activation in most human cancers. While direct telomerase inhibition is being explored as a therapeutic strategy, alternative strategies to target regulators of telomerase that could disrupt telomere mai...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2011-05, Vol.71 (9), p.3328-3340
Main Authors: ANTONIETTA CERONE, Maria, BURGESS, Darren J, NACEUR-LOMBARDELLI, Cristina, LORD, Christopher J, ASHWORTH, Alan
Format: Article
Language:English
Subjects:
Antineoplastic agents
Biological and medical sciences
Gene Silencing
HeLa Cells
High-Throughput Screening Assays - methods
Humans
Medical sciences
Pharmacology. Drug treatments
Phosphotransferases - genetics
Phosphotransferases - metabolism
RNA Interference
RNA, Small Interfering - genetics
Telomerase - genetics
Telomerase - metabolism
Telomere - genetics
Telomere - metabolism
Transfection
Tumors
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Summary:Telomerase is considered an attractive anticancer target on the basis of its common and specific activation in most human cancers. While direct telomerase inhibition is being explored as a therapeutic strategy, alternative strategies to target regulators of telomerase that could disrupt telomere maintenance and cancer cell proliferation are not yet available. Here, we report the findings of a high-throughput functional RNA interference screen to globally profile the contribution of kinases to telomerase activity (TA). This analysis identified a number of novel telomerase modulators, including ERK8 kinase, whose inhibition reduces TA and elicited characteristics of telomere dysfunction. Given that kinases represent attractive drug targets, we addressed the therapeutic implications of our findings, such as demonstrating how limiting TA via kinase blockade could sensitize cells to inhibition of the telomere-associated protein tankyrase. Taken together, our findings suggest novel combinatorial approaches to targeting telomere maintenance as a strategy for cancer therapy.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-10-2734