Molecular Mechanisms of Prostate Cancer Progression
Final rept. 19 Dec 2001-31 Dec 2005
VIRGINIA COMMONWEALTH UNIV RICHMOND
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To define the mechanisms involved in prostate cancer progression we have found that molecular chaperones are elevated causing increased telomerase activity. In order to determine the importance of the chaperones during prostate cancer progression we proposed 2 specific aims 1-define whether ectopic chaperone expression results in transformation and 2-determine whether chaperones are targets for prostate cancer therapy. The hsf-1 transcription factor was over-expressed in non-tumorigenic prostate cells resulting in increased hsp90 and hsp70 expression an upregulation of telomerase through a global chaperone increase and no effect on tumorigenicity. Using both a pharmacologic radicicol and genetic siRNA approaches depletion of functional Hsp90 in prostate cancer cells 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 prostate cancer.
- Anatomy and Physiology
- Medicine and Medical Research