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Targeting geranylgeranylation reduces adrenal gland tumor burden in a murine model of prostate cancer metastasis

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Abstract

The isoprenoid biosynthetic pathway (IBP) is critical for providing substrates for the post-translational modification of proteins key in regulating malignant cell properties, including proliferation, invasion, and migration. Inhibitors of the IBP, including statins and nitrogenous bisphosphonates, are used clinically for the treatment of hypercholesterolemia and bone disease respectively. The statins work predominantly in the liver, while the nitrogenous bisphosphonates are highly sequestered to bone. Inhibition of the entire IBP is limited by organ specificity and side effects resulting from depletion of all isoprenoids. We have developed a 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 selectively targets geranylgeranyl diphosphate synthase, reducing post-translational protein geranylgeranylation. Intracardiac injection of luciferase-expressing human-derived 22Rv1 PCa cells into SCID mice resulted in tumor development in bone (100 %), adrenal glands (72 %), mesentery (22 %), liver (17 %), and the thoracic cavity (6 %). Three weeks after tumor inoculation, daily subcutaneous (SQ) injections of 1.5 mg/kg GGOHBP or the vehicle were given for one month. Dissected tumors revealed a reduction in adrenal gland tumors corresponding to a 54 % (P < 0.005) reduction in total adrenal gland tumor weight of the treated mice as compared to vehicle-treated controls. Western blot analysis of the harvested tissues showed a reduction in Rap1A geranylgeranylation in adrenal glands and mesenteric tumors of the treated mice while non-tumorous tissues and control mice showed no Rap1A alteration. Our findings detail a novel bisphosphonate compound capable of preferentially altering the IBP in tumor-burdened adrenal glands of a murine model of PCa metastasis.

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Acknowledgments

We would like to thank Nadine Bannick for her support in utilizing the bioluminescence imager and James E Dunford for graciously providing the GGDPS enzyme. This project was supported in part by the Roy J. Carver Charitable Trust, the Roland W. Holden Family Program for Experimental Therapeutics.

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  1. Jeffrey D. Neighbors

    Present address: Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA, USA

Authors and Affiliations

  1. Department of Pharmacology, University of Iowa, Iowa City, IA, 55242-1294, USA

    Jacqueline E. Reilly & Raymond J. Hohl

  2. Department of Chemistry, University of Iowa, Iowa City, IA, 55242-1294, USA

    Jeffrey D. Neighbors

  3. Department of Molecular Physiology and Biophysics and Pathology and Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, 55242-1294, USA

    Michael D. Henry

  4. Department of Internal Medicine, University of Iowa, Iowa City, IA, 55242-1294, USA

    Huaxiang Tong & Raymond J. Hohl

  5. Departments of Medicine and Pharmacology, Pennsylvania State University Hershey Cancer Institute, 500 University Dr, Hershey, PA, 17033, USA

    Raymond J. Hohl

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  1. Jacqueline E. Reilly
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  2. Jeffrey D. Neighbors
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Correspondence to Raymond J. Hohl.

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Reilly, J.E., Neighbors, J.D., Tong, H. et al. Targeting geranylgeranylation reduces adrenal gland tumor burden in a murine model of prostate cancer metastasis. Clin Exp Metastasis 32, 555–566 (2015). https://doi.org/10.1007/s10585-015-9727-0

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