Targeting protein geranylgeranylation slows tumor development in a murine model of prostate cancer metastasis

ABSTRACT

The isoprenoid biosynthetic pathway (IBP) plays a critical role in providing substrates and enzymes necessary for the post-translational modification and thus activation of a number of proteins involved in prostate cancer metastasis. Previous work by our lab found novel compound disodium [(6Z,11E,15E)-9-[bis(sodiooxy)phosphoryl]−17-hydroxy-2,6,12,16-tetramethyheptadeca-2,6,11,15-tetraen-9-yl]phosphonate (GGOHBP), which inhibits the IBP enzyme geranylgeranyl diphosphate synthase (GGDPS), reduced protein geranylgeranylation without altering protein farnesylation. This activity significantly reduced adrenal gland tumor burden in a murine model of human prostate cancer metastasis which relied on treatment of established disease. The present study determined the ability of GGDPS inhibition to slow the development of prostate cancer metastasis in a preventative murine model. Using tail vein injection of human derived PC-3 prostate cancer cells 4 d after initiating daily GGOHBP or vehicle treatments, we found GGOHBP significantly reduced whole body tumor burden, significantly slowed the development of tumors, and prolonged overall survival as compared to vehicle treated animals. The observed reduction in soft tissue tumor burden corresponded to a biochemical reduction in Rap1A geranylgeranylation, which for prostate cancer is important in its own merit and which serves as a surrogate marker for Rho family, i.e. Rac, protein modification. This effect was present in all treated mice pointing to strong target engagement, which was not observed in non-tumor burdened tissues or control mice. Our findings reiterate a role for protein geranylgeranylation in the development of prostate cancer metastasis in vivo.

KEYWORDS:

• Drug development
• drug validation
• isoprenoid biosynthetic pathway
• prostate cancer metastasis
• post-translational modification

Disclosure of potential conflicts of interest

Ray Hohl and Jeffrey Neighbors are named as inventors on patents held by the University of Iowa Research Foundation that describe preparation of some GGDPS inhibitors as well as their use as potential anti-cancer agents. We are also founders of the company Terpenoid Therapeutics, Inc. and hold equity interest in this company.

Acknowledgments

The authors would like to thank Professor James E. Dunford at the University of Oxford for kindly providing the GGDPS enzyme. DGBP and GGOHBP were supplied by Terpenoid Therapeutics Inc. Coralville, IA.

Funding

The National Institute of Health Pharmacological Sciences Training Grant T32 GM067795 supported this work. This project was supported in part by the Roy J. Carver Charitable Trust, the Roland W. Holden Family Program for Experimental Therapeutics.