Synergistic tumor suppression by combined inhibition of telomerase and CDKN1A

Romi Gupta, Yuying Dong, Peter D. Solomon, Hiromi I. Wettersten, Christopher J. Cheng, JIn Na Min, Jeremy Henson, Shaillay Kumar Dogra, Sung H. Hwang, Bruce D. Hammock, Lihua J. Zhu, Roger R. Reddel, W. Mark Saltzman, Robert H Weiss, Sandy Chang, Michael R. Green, Narendra Wajapeyee

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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.

Original languageEnglish (US)
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number30
DOIs
StatePublished - 2014

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Gupta, R., Dong, Y., Solomon, P. D., Wettersten, H. I., Cheng, C. J., Min, JI. N., Henson, J., Dogra, S. K., Hwang, S. H., Hammock, B. D., Zhu, L. J., Reddel, R. R., Saltzman, W. M., Weiss, R. H., Chang, S., Green, M. R., & Wajapeyee, N. (2014). Synergistic tumor suppression by combined inhibition of telomerase and CDKN1A. Proceedings of the National Academy of Sciences of the United States of America, 111(30). https://doi.org/10.1073/pnas.1411370111