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.