Synergistic tumor suppression by combined inhibition of telomerase and CDKN1A
Authors
Gupta, RomiDong, Yuying
Solomon, Peter D.
Wettersten, Hiromi I.
Cheng, Christopher J.
Min, JIn-Na
Henson, Jeremy
Dogra, Shaillay Kumar
Hwang, Sung H.
Hammock, Bruce D.
Zhu, Lihua Julie
Reddel, Roger R.
Saltzman, W. Mark
Weiss, Robert H.
Chang, Sandy
Green, Michael R.
Wajapeyee, Narendra
Document Type
Journal ArticlePublication Date
2014-07-29
Metadata
Show full item recordAbstract
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 p21WAF1/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.Source
Gupta R, Dong Y, Solomon PD, Wettersten HI, Cheng CJ, Min JN, Henson J, Dogra SK, Hwang SH, Hammock BD, Zhu LJ, Reddel RR, Saltzman WM, Weiss RH, Chang S, Green MR, Wajapeyee N. Synergistic tumor suppression by combined inhibition of telomerase and CDKN1A. Proc Natl Acad Sci U S A. 2014 Jul 29;111(30):E3062-E3071. doi: 10.1073/pnas.1411370111. Link to article on publisher's siteDOI
10.1073/pnas.1411370111Permanent Link to this Item
http://hdl.handle.net/20.500.14038/44038PubMed ID
25024194Related Resources
Link to Article in PubMedRights
Publisher PDF posted as allowed by the publisher's author rights policy at http://www.pnas.org/site/aboutpnas/authorfaq.xhtml.
ae974a485f413a2113503eed53cd6c53
10.1073/pnas.1411370111