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

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)5308-5320
Number of pages13
JournalOncogene
Volume38
Issue number26
DOIs
StatePublished - Jun 27 2019

Fingerprint

Farnesyltranstransferase
Adenocarcinoma
Mucins
Unfolded Protein Response
Terpenes
Therapeutics
Apoptosis
Prenylation
Intracellular Membranes
Post Translational Protein Processing
Small Interfering RNA
Neoplasms
Cell Death
Up-Regulation
Carbon
Neoplasm Metastasis
Cell Line
Enzymes
Growth

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Inhibition of geranylgeranyl diphosphate synthase is a novel therapeutic strategy for pancreatic ductal adenocarcinoma. / Haney, Staci L.; Varney, Michelle L.; Chhonker, Yashpal S.; Shin, Simon; Mehla, Kamiya; Crawford, Ayrianne J.; Smith, Heather Jensen; Smith, Lynette M; Murry, Daryl J; Hollingsworth, Michael A; Holstein, Sarah A.

In: Oncogene, Vol. 38, No. 26, 27.06.2019, p. 5308-5320.

Research output: Contribution to journalArticle

Haney, Staci L. ; Varney, Michelle L. ; Chhonker, Yashpal S. ; Shin, Simon ; Mehla, Kamiya ; Crawford, Ayrianne J. ; Smith, Heather Jensen ; Smith, Lynette M ; Murry, Daryl J ; Hollingsworth, Michael A ; Holstein, Sarah A. / Inhibition of geranylgeranyl diphosphate synthase is a novel therapeutic strategy for pancreatic ductal adenocarcinoma. In: Oncogene. 2019 ; Vol. 38, No. 26. pp. 5308-5320.
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AU - Varney, Michelle L.

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AU - Shin, Simon

AU - Mehla, Kamiya

AU - Crawford, Ayrianne J.

AU - Smith, Heather Jensen

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AU - Murry, Daryl J

AU - Hollingsworth, Michael A

AU - Holstein, Sarah A

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