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Inhibition of geranylgeranyl diphosphate synthase is a novel therapeutic strategy for pancreatic ductal adenocarcinoma

Oncogene volume 38, pages 5308–5320 (2019)Cite this article

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Abstract

Rab proteins play an essential role in regulating intracellular membrane trafficking processes. Rab activity is dependent upon geranylgeranylation, a post-translational modification that involves the addition of 20-carbon isoprenoid chains via the enzyme geranylgeranyl transferase (GGTase) II. We have focused on the development of inhibitors against geranylgeranyl diphosphate synthase (GGDPS), which generates the isoprenoid donor (GGPP), as anti-Rab agents. Pancreatic ductal adenocarcinoma (PDAC) is characterized by abnormal mucin production and these mucins play important roles in tumor development, metastasis and chemo-resistance. We hypothesized that GGDPS inhibitor (GGDPSi) treatment would induce PDAC cell death by disrupting mucin trafficking, thereby inducing the unfolded protein response pathway (UPR) and apoptosis. To this end, we evaluated the effects of RAM2061, a potent GGDPSi, against PDAC. Our studies revealed that GGDPSi treatment activates the UPR and triggers apoptosis in a variety of human and mouse PDAC cell lines. Furthermore, GGDPSi treatment was found to disrupt the intracellular trafficking of key mucins such as MUC1. These effects could be recapitulated by incubation with a specific GGTase II inhibitor, but not a GGTase I inhibitor, consistent with the effect being dependent on disruption of Rab-mediated activities. In addition, siRNA-mediated knockdown of GGDPS induces upregulation of UPR markers and disrupts MUC1 trafficking in PDAC cells. Experiments in two mouse models of PDAC demonstrated that GGDPSi treatment significantly slows tumor growth. Collectively, these data support further development of GGDPSi therapy as a novel strategy for the treatment of PDAC.

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Acknowledgements

This work was supported by the Fred & Pamela Buffett Cancer Center Support Grant from the National Cancer Institute under award P30 CA036727 and the National Institutes of Health P50CA127297. The authors wish to acknowledge the support of the Fred & Pamela Buffett Cancer Center Advanced Microscopy Core Facility and the Flow Cytometry Research Facility, supported by the National Cancer Institute under award P30 CA036727. We thank Janice A. Taylor and James R. Talaska of the Advanced Microscopy Core Facility for providing assistance with confocal microscopy.

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Authors and Affiliations

  1. Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA

    Staci L. Haney, Michelle L. Varney & Sarah A. Holstein

  2. Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA

    Staci L. Haney, Michelle L. Varney, Simon Shin, Kamiya Mehla, Ayrianne J. Crawford, Heather Jensen Smith, Daryl J. Murry, Michael A. Hollingsworth & Sarah A. Holstein

  3. Department of Pharmacy Practice, University of Nebraska Medical Center, Omaha, NE, USA

    Yashpal S. Chhonker & Daryl J. Murry

  4. Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, NE, USA

    Simon Shin, Kamiya Mehla, Ayrianne J. Crawford, Heather Jensen Smith & Michael A. Hollingsworth

  5. College of Public Health, University of Nebraska Medical Center, Omaha, NE, USA

    Lynette M. Smith

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Correspondence to Sarah A. Holstein.

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Haney, S.L., Varney, M.L., Chhonker, Y.S. et al. Inhibition of geranylgeranyl diphosphate synthase is a novel therapeutic strategy for pancreatic ductal adenocarcinoma. Oncogene 38, 5308–5320 (2019). https://doi.org/10.1038/s41388-019-0794-6

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