Document Type

Dissertation

Date of Degree

Fall 2014

Degree Name

PhD (Doctor of Philosophy)

Degree In

Pharmacology

First Advisor

Raymond J. Hohl

Abstract

The isoprenoid biosynthetic pathway (IBP) has been highly implicated in a number of cellular malignancies, including proliferation, invasion, and migration. Epidemiological studies have found clinically relevant inhibitors of the IBP, such as the statin family and nitrogenous bisphosphonates, reduce the risk of prostate cancer advancement. In vitro work has implicated statin's and nitrogenous bisphosphonate's inhibition of GGPP and protein geranylgeranylation as the components responsible for their reduction of prostate cancer progression. However, their depletion of nearly all isoprenoid intermediates as well as their organ specificities make understanding the specific role of protein geranylgeranylation in prostate cancer metastasis impossible.

Consequently, we have developed a novel library of seven alkyl bisphosphonate ethers found to potently reduce GGDPS with little to no activity against the related FDPS enzyme. Inhibition of GGDPS in three human prostate cancer cell lines reduced GGPP and protein geranylgeranylation without affecting protein farnesylation, translating into a reduction in cell migration and invasion. Interestingly, the GGDPS inhibitors reduced protein geranylgeranylation at lower concentrations in the highly metastatic PC3 cell line as compared to the less metastatic LNCaP and 22Rv1 cell lines. Additionally, the PC3 cell line was found to have higher levels of endogenous IBP intermediates as compared to the less metastatic cells. Translation in vivo using two murine models of human prostate cancer metastasis found a reduction in soft tissue tumor burden that corresponded to a biochemical reduction in protein geranylgeranylation. In conclusion, selective reduction of GGPP and protein geranylgeranylation was sufficient to reduce the metastatic potential of prostate cancer in vitro and in vivo.

Public Abstract

Prostate cancer is the most common cancer in men, with nearly 30,000 people dying each year. In spite of significant advancements in the treatment of local and regional prostate cancer, the metastatic form continues to have dire outcomes with a five-year survival rate of only 28%. Consequently, an effective novel treatment against metastatic prostate cancer is critically needed.

Multiple epidemiological studies of men with prostate cancer have found inhibition of the isoprenoid biosynthetic pathway (IBP) by the clinically available statins and nitrogenous bisphosphonates was capable of reducing the risk of advanced prostate cancer. Follow-up work found statin’s and nitrogenous bisphosphonate’s ability to reduce protein geranylgeranylation was the component responsible for their reduction of prostate cancer progression. However, statins and nitrogenous bisphosphonates deplete nearly the entire IBP and are limited by organ specificity in humans. Consequently, we have developed a novel library of compounds capable of specifically depleting protein geranylgeranylation, allowing us to further study the role of protein geranylgeranylation in prostate cancer metastasis as well as test them as novel treatment options.

We found depletion of protein geranylgeranylation by the novel compounds translated into a reduction in human prostate cancer cell migration and invasion. Additionally, two mouse models of human prostate cancer metastasis found one novel inhibitor of protein geranylgeranylation reduced established soft tissues tumors and slowed the development of new tumors while increasing overall survival. In conclusion, we found a reduction in protein geranylgeranylation by the novel inhibitors was sufficient to reduce metastatic prostate cancer.

Keywords

publicabstract, bisphosphonates, experimental therapeutics, geranylgeranylation, isoprenoid biosynthetic pathway, metastasis, prostate cancer

Pages

xiii, 148 pages

Bibliography

Includes bibliographical references (pages 140-148).

Copyright

Copyright 2014 Jacqueline Erin Reilly

Included in

Pharmacology Commons

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