The relationship between innate immunity and tumor suppression is the focus of this laboratory. Understanding the molecular mechanisms of interferon (IFN) action against cancer cells and viruses is the long-range goal. The IFNs are a family of pleiotropic cytokines responsible for providing innate immunity against a wide-range of viruses and other microbial pathogens. Moreover, IFNs regulate cell proliferation, apoptosis and immune responses, properties that underlie their uses in the treatment of cancer. IFNs alter patterns of gene expression in cells by binding to specific cell surface receptors and activating JAK/STAT signal transduction pathways. The IFN-stimulated genes (ISGs) encode proteins that mediate the biological effects of IFNs. Among the most highly inducible proteins are a family of 2',5'-oligoadenylate synthetases (OAS) that are activated by double-stranded RNA (dsRNA) to produce 2',5'-oligoadenylates (2-5A) of the general formula [pppA(2'p5'A)n, n>2]. The function of 2-5A is to activate RNase L, a uniquely-regulated enzyme that we cloned.
Recent progress from the laboratory has contributed to our understanding of the basic events underlying the tumor suppressor and antiviral activities of the 2-5A system. The absence of RNase L in mice leads to enhanced susceptibility to viral infections and to a defect in apoptosis (programmed cell death). Therefore, the 2-5A system probably eliminates virus-infected cells through the induction of apoptosis. In addition, we showed that RNase L participates in non-viral apoptotic pathways. We reported that transient activation of RNase L has a profound effect on gene expression. Remarkably, 2-5A activation of RNase L induces twice as many mRNA species as it downregulates, including many antiviral genes. Therefore, the transcriptional induction of antiviral genes likely contributes to the antiviral activities of RNase L.
Recent studies suggest a role for RNase L in suppression of prostate cancer. The RNase L gene (RNASEL) is a candidate for the hereditary prostate cancer 1 (HPC1) gene. In addition, a novel gammaretrovirus, XMRV, was identified and cloned from prostates bearing tumors. XMRV was almost exclusively found in patients that are germline homozygous for the R462Q reduced acitivty variant of RNase L. Our goals in these studies are to probe the fundamental roles of RNase L and XMRV in tumor biology and to explore their clinical significance.
By using DNA microarray technology, we identified many novel interferon-regulated genes. One of these genes encodes phospholipid scramblase 1 (PLSCR1), a calcium-dependent protein linked to the transbilayer movement of phospholipids. The role of PLSCR1 induction in the antiviral and anticancer activity of IFNs is a current topic of investigation (in collaboration with Dr. Peter J. Sims). We have found that PLSCR1 inhibits viral replication and functions as a suppressor of human ovarian carcinoma in a mouse model. Therefore, an emerging theme of the laboratory is one of host viral defense genes that have dual roles in the suppression of tumor growth.
Urisman, A., Molinaro, R.J., Fischer, N., Plummer, S.J., Casey, G., Klein, E.A., Malathi, K., Magi-Galluzzi, C., Tubbs, R.R., Ganem, D., Silverman, R.H., and DeRisi, J. Identification of a novel gammaretrovirus in prostate tumors of patients homozygous for R462Q RNase L variant. PLos Pathogens, 2(3):e25. Epub 2006. [PubMed]
Zhou, A., Molinaro, R.J., Malathi, K., and Silverman, R.H. Mapping of the human RNASEL promoter and expression in cancer and normal cells. J. Interferon & Cyt. Res., 25, 595-603, 2005. [PubMed]
Malathi, K., Paranjape, J.M., Bulanova, E., Shim, M., Guenther-Johnson, J.M., Faber, P.W., Eling, T.E., Williams, B.R.G., and Silverman, R.H. A novel transcriptional signaling pathway in the interferon system mediated by 2'-5'-oligoadenylate activation of RNase L. Proc. Natl. Acad. Sci. U.S.A., 102, 14533-14538, 2005. [PubMed]
Malathi, K., Paranjape, J.M., Ganapathi, R. and R.H. Silverman. HPC1/RNASEL mediates apoptosis of prostate cancer cells treated with 2',5'-oligoadenylates, topoisomerase I inhibitors and TRAIL. Cancer Res., 4:9144-10151, 2004. [PubMed]
Dong, B., Zhou, Q., Zhao, J. , Zhou, A., Harty, R.N., Bose, S., Banerjee, A., Guenther, J., Slee, Williams, B.R.G., Wiedmer, T., Sims, P.J. and Silverman, R.H. Phospholipid Scramblase 1 (PLSCR1) Markedly Potentiates The Antiviral Activity of Interferon, J. Virol., 78: 8983-8993 2004. [PubMed]
Xiang, Y., Wang, Z., Murakami, J., Plummer, S., Klein, E.A., Carpten, J., Trent, J., Isaacs W., Casey, G., and Silverman, R. H. Effects Of RNase L Mutations Associated With Prostate Cancer On Apoptosis Induced By 2’,5’-Oligoadenylates. Cancer Res. 63: 6795-6801, 2003. [PubMed]
Carpten, J., et al. Germline Mutations in the Ribonuclease L (RNase L) Gene in Hereditary Prostate Cancer 1 (HPC1) -Linked Families. Nature Genetics 30: 181-184, 2002.