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J. Biol. Chem., Vol. 280, Issue 25, 23709-23717, June 24, 2005

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Cellular and Gene Expression Responses Involved in the Rapid Growth Inhibition of Human Cancer Cells by RNA Interference-mediated Depletion of Telomerase RNA^*

Shang Li, Julia Crothers, Christopher M. Haqq, and Elizabeth H. Blackburn¶

From the Departments of Biochemistry and Biophysics, and Medicine, University of California, San Francisco, San Francisco, California 94143

Inhibition of the up-regulated telomerase activity in cancer cells has previously been shown to slow cell growth but only after prior telomere shortening. Previously, we have reported that, unexpectedly, a hairpin short interfering RNA specifically targeting human telomerase RNA rapidly inhibits the growth of human cancer cells independently of p53 or telomere length and without bulk telomere shortening (Li, S., Rosenberg, J. E., Donjacour, A. A., Botchkina, I. L., Hom, Y. K., Cunha, G. R., and Blackburn, E. H. (2004) Cancer Res. 64, 4833–4840). Here we have demonstrated that such telomerase RNA knockdown in cancer cells does not cause telomere uncapping but rather induces changes in the global gene expression profile indicative of a novel response pathway, which includes suppression of specific genes implicated in angiogenesis and metastasis, and is distinct from the expression profile changes induced by telomere-uncapping mutant template telomerase RNAs. These cellular responses to depleting telomerase in human cancer cells together suggest that cancer cells are "telomerase-addicted" and uncover functions of telomerase in tumor growth and progression in addition to telomere maintenance.

Received for publication, March 14, 2005

^* This work was supported by grants from the NCI, National Institutes of Health, the Steven and Michele Kirsch Foundation, and CaPCURE (to E. H. B.), a Damon Runyon Cancer Research Foundation Postdoctoral Fellowship (to S. L.), and the Dale A. Smith family. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

^¶ To whom correspondence should be addressed. Tel.: 415-476-4912; Fax: 415-514-2913; E-mail: telomer{at}itsa.ucsf.edu.

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