Recently, the interferon (IFN) antiviral pathways and prostate cancer genetics and have surprisingly converged on ribonuclease L (RNase L), a uniquely regulated enzyme that requires 5'-triphosphoryl, 2',5'- linked oligoadenylates (2-5A) for its activity. The presence of both germline mutations in RNASEL segregating with disease within hereditary prostate cancer 1 (HPC1)-affected families and loss of heterozygosity (LOH) in tumor tissues point to a novel role for RNase L in the pathogenesis of prostate cancer. Our preliminary data implicate RNase L in mediating prostate cancer cell apoptosis and suggest that RNase L functions as a tumor suppressor in mice. We propose to study the fundamental role of RNase L in prostate cancer using cell culture and animal models and in RNA isolated from prostate cancer patients. Our hypothesis is that RNase L suppresses development of prostate cancer by affecting the balance between cell growth and apoptosis.
Our specific aims are to: (1) study regulation of the 2-5A/RNase L system by IFN and androgen in prostate cancer cells and to identify viral and/or cellular RNA activators of 2-5A synthetase in prostate tumor RNA; (2) downregulate RNase L and RNase L inhibitor (RLI) levels with short interfering RNAs (siRNAs) in prostate cancer cells prior to viral infection, dsRNA treatment or androgen deprivation and probe the apoptotic signaling pathway; and (3) study the effect of RNase L on prostate biology in mice that are wild type or deficient in RNASEL in combination with loss of other genes implicated in prostate cancer pathogenesis (p53 and NKX3.1) or dsRNA mediated apoptosis (protein kinase PKR). Mapping of HPC1 to RNASEL and the association of RNASEL mutations with prostate cancer risk provide the justification for these studies. The experiments described in this PROPOSAL describe a previously unexplored area of research that may bring us closer to the eventual goal of understanding a molecular basis for prostate cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA103943-04
Application #
7171854
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Jhappan, Chamelli
Project Start
2004-02-16
Project End
2009-01-31
Budget Start
2007-02-01
Budget End
2008-01-31
Support Year
4
Fiscal Year
2007
Total Cost
$297,398
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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