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Proc Natl Acad Sci U S A. 2014 Jul 29;111(30):E3062-71. doi: 10.1073/pnas.1411370111. Epub 2014 Jul 14.

Synergistic tumor suppression by combined inhibition of telomerase and CDKN1A.

Author information

1
Departments of Pathology and.
2
Division of Nephrology, Department of Internal Medicine, University of California, Davis, California 95616;
3
Departments of Biomedical Engineering andMolecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511;
4
Departments of Pathology andLaboratory Medicine, Yale University School of Medicine, New Haven, CT 06510;
5
Sydney Medical School, University of Sydney, NSW 2006, Australia;Cancer Research Unit, Children's Medical Research Institute, Westmead, NSW 2145, Australia;
6
Singapore Institute of Clinical Sciences, Agency for Science Technology and Research (A*STAR), Brenner Center for Molecular Medicine, Singapore 117609;
7
Department of Entomology and.
8
Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Massachusetts 01605; and.
9
Departments of Biomedical Engineering and.
10
Division of Nephrology, Department of Internal Medicine, University of California, Davis, California 95616;Department of Medicine, Mather VA Medical Center, Sacramento, CA 9565.
11
Howard Hughes Medical Institute and Narendra.Wajapeyee@yale.edu Michael.Green@umassmed.edu.
12
Departments of Pathology and Narendra.Wajapeyee@yale.edu Michael.Green@umassmed.edu.

Abstract

Tumor suppressor p53 plays an important role in mediating growth inhibition upon telomere dysfunction. Here, we show that loss of the p53 target gene cyclin-dependent kinase inhibitor 1A (CDKN1A, also known as p21(WAF1/CIP1)) increases apoptosis induction following telomerase inhibition in a variety of cancer cell lines and mouse xenografts. This effect is highly specific to p21, as loss of other checkpoint proteins and CDK inhibitors did not affect apoptosis. In telomerase, inhibited cell loss of p21 leads to E2F1- and p53-mediated transcriptional activation of p53-upregulated modulator of apoptosis, resulting in increased apoptosis. Combined genetic or pharmacological inhibition of telomerase and p21 synergistically suppresses tumor growth. Furthermore, we demonstrate that simultaneous inhibition of telomerase and p21 also suppresses growth of tumors containing mutant p53 following pharmacological restoration of p53 activity. Collectively, our results establish that inactivation of p21 leads to increased apoptosis upon telomerase inhibition and thus identify a genetic vulnerability that can be exploited to treat many human cancers containing either wild-type or mutant p53.

PMID:
25024194
PMCID:
PMC4121806
DOI:
10.1073/pnas.1411370111
[Indexed for MEDLINE]
Free PMC Article

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