Cancer 2013 May (2)-2

Betulinic acid selectively increases protein degradation and enhances prostate cancer-specific apoptosis: possible role for inhibition of deubiquitinase activity.

PLoS One. 2013;8(2):e56234.

Reiner T, Parrondo R, de Las Pozas A, Palenzuela D, Perez-Stable C.

Geriatric Research, Education, and Clinical Center and Research Service, Bruce W. Carter Veterans Affairs Medical Center, Miami, Florida, United States of America.

Abstract

Inhibition of the ubiquitin-proteasome system (UPS) of protein degradation is a valid anti-cancer strategy and has led to the approval of bortezomib for the treatment of multiple myeloma. However, the alternative approach of enhancing the degradation of oncoproteins that are frequently overexpressed in cancers is less developed. Betulinic acid (BA) is a plant-derived small molecule that can increase apoptosis specifically in cancer but not in normal cells, making it an attractive anti-cancer agent. Our results in prostate cancer suggested that BA inhibited multiple deubiquitinases (DUBs), which resulted in the accumulation of poly-ubiquitinated proteins, decreased levels of oncoproteins, and increased apoptotic cell death. In normal fibroblasts, however, BA did not inhibit DUB activity nor increased total poly-ubiquitinated proteins, which was associated with a lack of effect on cell death. In the TRAMP transgenic mouse model of prostate cancer, treatment with BA (10 mg/kg) inhibited primary tumors, increased apoptosis, decreased angiogenesis and proliferation, and lowered androgen receptor and cyclin D1 protein. BA treatment also inhibited DUB activity and increased ubiquitinated proteins in TRAMP prostate cancer but had no effect on apoptosis or ubiquitination in normal mouse tissues. Overall, our data suggests that BA-mediated inhibition of DUBs and induction of apoptotic cell death specifically in prostate cancer but not in normal cells and tissues may provide an effective non-toxic and clinically selective agent for chemotherapy.

PMID: 23424652

Additional summary:

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.

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