Research Interests:

A large protein complex in the cell, termed the 26S proteasome, is responsible for the bulk of protein degradation. The proteins that are degraded include those that are damaged, mis-folded, or that are specifically targeted in order to carry out a biological activity. It has been hypothesized that cancer cells could target specific proteins for degradation to confer survival. As evidence for this theory, a proteasome inhibitor, Velcade, has been developed to treat cancer patients. Velcade is currently used to treat multiple myeloma and is also being evaluated on individuals with advanced prostate cancer. This drug has efficacy, as it reduces tumor burden in about half of the patients; however, it does not normally eliminate the cancer. An additional shortcoming of the current proteasome inhibition therapy is that it is unclear which tumors will respond to the treatment. Furthermore, Velcade is not tumor cell specific as it blocks the proteasome activities in every cell, not just the functions responsible for cancer progression. 

Our goal is to improve upon the promise of proteasome inhibition strategies by understanding how Velcade alters the pathways that lead to tumor cell death. To this end, we have been analyzing a mechanism of cell death that is initiated by a specific class of proteins present outside of the cell, termed tumor necrosis factor cytokines. Upon proteasome inhibition, cancer cells that are normally resistant to this death receptor-mediated apoptosis now rapidly die. 

Our studies incorporate human, animal and biochemical approaches. In collaboration with clinicians at the Markey Cancer Center we are determining if multiple myeloma cancer cells taken directly from patients can be made sensitive to death receptor-mediated apoptosis by Velcade. This assay could provide a basis for determining those patients who will respond to Velcade and provide a novel treatment to increase the Velcade response rate. Using mouse tumor models we have recently demonstrated the proof of principle for combining Velcade with a death receptor agonist in vivo and are further adapting this strategy for patient application. Through in vitro approaches we are identifying the individual components of the ubiquitin proteasome pathway responsible for regulating the sensitivity to death receptor-mediated apoptosis. We have identified two proteins (ubiquitin ligases) that negatively regulate caspase-8, an enzyme that initiates death receptor apoptosis. We are defining the importance of these two ubiquitin ligases in mediating cell death and caspase-8 activity. Importantly, designing a specific strategy to confer caspase-8 activation in tumor cells may lead to the next generation of proteasome inhibitors.

REPRESENTATIVE PUBLICATIONS:

Thorpe, J.A., Christian, P.A., and S.R. Schwarze. In press. Proteasome inhibition blocks caspase-8 degradation and sensitizes prostate cancer cells to death receptor-mediated apoptosis. 

F.C. Peterson, J.A. Thorpe, A. Harder, B.F. Volkman, and S.R. Schwarze. 2006. Structural Determinants Involved in the Regulation of CXCL14/BRAK Expression by the 26S Proteasome. J. Mol.Biol. 363:813-22. 

S.R. Schwarze, V.X Fu, J.A. Desotelle, M.L. Kenowski, and D.F. Jarrard. 2005. The identification of senescence-specific genes during the induction of senescence in prostate cancer cells. Neoplasia. 9:816-23.

S.R. Schwarze, J. Luo, W.B. Isaacs, and D.F. Jarrard. 2005. Modulation of CXCL14/BRAK expression in prostate cancer. Prostate. 64:67-74.

V.X. Fu, S.R. Schwarze, M.L. Kenowski, S. LeBlanc, J. Svaren, and D.F. Jarrard. 2004. A loss of insulin-like growth factor 2 imprinting is modulated by CCCTC-binding factor down-regulation at senescence in human epithelial cells. J. Biol. Chem. 279:55518-26.

V.X. Fu, S.R. Schwarze, C.A. Reznikoff, and D.F. Jarrard. 2003. The establishment and characterization of transitional cell cancer in vitro. In: Freshney, RI and Pfagner, R. The Culture of Human Tumor Cells. Wiley and Sons.

S.R. Schwarze, V.X. Fu, and D.F. Jarrard. 2003. Cdc37 enhances proliferation and is necessary for normal human prostate epithelial cell survival. Cancer Res. 63:4614-9. 

S.R. Schwarze, S.E. DePrimo, L.M. Grabert, V.X. Fu, J.D. Brooks, and D.F. Jarrard.  2002.  Novel pathways associated with bypassing cellular senescence in human prostate epithelial cells. J. Biol. Chem. 277:14877-83. 

S.R. Schwarze, Y. Shi, V.X. Fu, P.A Watson, and D.F. Jarrard. 2001. Role of cyclin-dependent kinase inhibitors in the growth arrest at senescence in human prostate epithelial and uroepithelial cells. Oncogene. 20:8184-92.