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Molecular and Cellular Biology, February 2006, p. 1452-1462, Vol. 26, No. 4
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.4.1452-1462.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Induction of Nitric Oxide Synthase-Dependent Telomere Shortening after Functional Inhibition of Hsp90 in Human Tumor Cells

Sarah A. Compton,^1, Lynne W. Elmore,² Kimberly Haydu,² Colleen K. Jackson-Cook,^2,3,4 and Shawn E. Holt^1,2,3,4*

Department of Pharmacology and Toxicology,¹ Department of Pathology,² Department of Human Genetics,³ Massey Cancer Center, Medical College of Virginia at Virginia Commonwealth University, 1101 E. Marshall St., Richmond, Virginia 23298-0662⁴

Received 25 July 2005/ Returned for modification 4 October 2005/ Accepted 18 November 2005

In most cancer cells, the lengths of telomeres, the functional DNA-protein complexes located at chromosome ends, are maintained by the ribonucleoprotein telomerase. Hsp90 facilitates the assembly of telomerase and remains associated with the functional complex, implying a direct involvement of Hsp90 in telomere length regulation. In an effort to elucidate the effects of Hsp90 inhibition on function and viability of human prostate cancer cells, both pharmacological (radicicol) and genetic (small interfering RNA) approaches were utilized to target Hsp90. Depletion of functional Hsp90 caused dramatic telomere shortening followed by apoptosis. Of particular significance, these cells exhibit a high level of nitric oxide synthase (NOS)-dependent free radical production, and simultaneous treatment of cells with the NOS inhibitor L-NAME resulted in telomere elongation and prevention of apoptosis. In addition, we observe significant DNA damage assessed by telomere dysfunction, although in the absence of a classical DNA damage response. Overall, our data suggest a novel mechanism whereby inhibition of Hsp90 disrupts free radical homeostasis and contributes directly to telomere erosion, further implicating Hsp90 as a potential therapeutic target for cancer cells.

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* Corresponding author. Mailing address: Department of Pharmacology and Toxicology, Medical College of Virginia, 1101 E. Marchall St., Richmond, VA 23298-0662. Phone: (804) 827-0458. Fax: (804) 828-5598. E-mail: seholt{at}vcu.edu.

Present address: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, N.C.

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Molecular and Cellular Biology, February 2006, p. 1452-1462, Vol. 26, No. 4
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.4.1452-1462.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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