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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Jhappan, Chamelli
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
United States
Zip Code
Lee, Deanna; Das Gupta, Jaydip; Gaughan, Christina et al. (2012) In-depth investigation of archival and prospectively collected samples reveals no evidence for XMRV infection in prostate cancer. PLoS One 7:e44954
Onlamoon, Nattawat; Das Gupta, Jaydip; Sharma, Prachi et al. (2011) Infection, viral dissemination, and antibody responses of rhesus macaques exposed to the human gammaretrovirus XMRV. J Virol 85:4547-57
Dong, Beihua; Silverman, Robert H (2010) Androgen stimulates transcription and replication of xenotropic murine leukemia virus-related virus. J Virol 84:1648-51
Kim, Sanggu; Rusmevichientong, Alice; Dong, Beihua et al. (2010) Fidelity of target site duplication and sequence preference during integration of xenotropic murine leukemia virus-related virus. PLoS One 5:e10255
Silverman, Robert H; Nguyen, Carvell; Weight, Christopher J et al. (2010) The human retrovirus XMRV in prostate cancer and chronic fatigue syndrome. Nat Rev Urol 7:392-402
Sakuma, Ryuta; Sakuma, Toshie; Ohmine, Seiga et al. (2010) Xenotropic murine leukemia virus-related virus is susceptible to AZT. Virology 397:1-6
Qiu, Xiaoxing; Swanson, Priscilla; Luk, Ka-Cheung et al. (2010) Characterization of antibodies elicited by XMRV infection and development of immunoassays useful for epidemiologic studies. Retrovirology 7:68
Dong, Beihua; Silverman, Robert H; Kandel, Eugene S (2008) A natural human retrovirus efficiently complements vectors based on murine leukemia virus. PLoS One 3:e3144
Kim, Sanggu; Kim, Namshin; Dong, Beihua et al. (2008) Integration site preference of xenotropic murine leukemia virus-related virus, a new human retrovirus associated with prostate cancer. J Virol 82:9964-77
Larson, Benjamin T; Magi-Galluzzi, Cristina; Casey, Graham et al. (2008) Pathological aggressiveness of prostatic carcinomas related to RNASEL R462Q allelic variants. J Urol 179:1344-8

Showing the most recent 10 out of 14 publications