BERKELEY, CA (UroToday.com) - Prostate cancer (PC) is one of the leading causes of cancer-related death in men and remains incurable when metastasis to distant tissues occurs. Despite the initial response to androgen deprivation therapy, PC gradually progresses to an unresponsive stage. When this occurs, it is known as castration-resistant prostate cancer (CRPC). An important goal in research is to discover new chemotherapy agents that specifically kill cancer but leave non-cancer normal cells and tissues intact.
The work presented in this publication shows that betulinic acid (BA), a plant-derived small molecule, inhibits multiple deubiquitinases (DUBs) in PC, resulting in apoptosis or cell death. In contrast, BA has no effect on DUB activity in normal cells and tissues, resulting in no toxicity. DUBs function by removing the poly-ubiquitin marker that signals proteins for degradation by the ubiquitin-proteasome system (UPS), thus increasing the levels of pro-survival proteins and making cancer cells more difficult to kill by chemotherapy. Inhibition of DUBs increases poly-ubiquitination and UPS-mediated degradation of proteins important for the proliferation and survival of cancer cells, thus resulting in cell death.
Our data shows that BA inhibits the growth of PC in a mouse model of CRPC and in human PC cells in culture. By inhibiting DUB activity in PC, BA treatment increases poly-ubiquitin and reduces several proliferation and pro-survival proteins, including androgen receptor (AR), the most important protein in the emergence of CRPC. In non-cancer cells and tissues, BA treatment does not increase poly-ubiquitin and there is no effect on cell death. Our hypothesis is that inhibition of specific DUBs in PC, but not in non-cancer cells, stimulates selective protein degradation and increases tumor-specific cell death.
Further work is required to determine whether high levels of specific DUBs in PC distinguishes them from normal cells and allows BA to function as a cancer-specific therapeutic agent. We will investigate the new idea that inhibition of DUBs will specifically induce death in PC but not in non-cancer cells. Targeting of specific DUBs may expose a weakness in PC cells that is not required for normal cells. Therefore, there is the potential to identify an effective, non-toxic, and clinically-selective agent such as BA for the treatment of CRPC. There is also the potential long-term impact of prolonging survival of patients with CRPC via the specific degradation of AR and other PC-specific, pro-survival proteins.
Carlos Perez-Stable, PhD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Geriatric Research, Education, and Clinical Center and Research Service, Bruce W. Carter Veterans Affairs Medical Center, Miami, Florida USA
Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida USA
Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida USA