Upregulation of endogenous farnesyl diphosphate synthase overcomes the inhibitory effect of bisphosphonate on protein prenylation in Hela cells

Subhajit Das, Peter A. Edwards, Julie C Crockett, Michael J. Rogers

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Nitrogen-containing bisphosphonates (N-BPs) such as zoledronic acid (ZOL) are the gold standard treatment for diseases of excessive bone resorption. N-BPs inactivate osteoclasts via inhibition of farnesyl diphosphate synthase (FPPS), thereby preventing the prenylation of essential small GTPases. Not all patients respond to N-BP therapy to the same extent, and some patients, for example with tumour-associated bone disease or Paget's disease, appear to develop resistance to N-BPs. The extent to which upregulation of FPPS might contribute to these phenomena is not clear. Using quantitative PCR and western blot analysis we show that levels of FPPS mRNA and protein can be upregulated in HeLa cells by culturing in lipoprotein deficient serum (LDS) or by over-expression of SREBP-1a. Upregulated, endogenous FPPS was predominantly localised to the cytosol and did not co-localise with peroxisomal or mitochondrial markers. Upregulation of endogenous FPPS conferred resistance to the inhibitory effect of low concentrations of ZOL on the prenylation of the small GTPase Rap1a. These observations suggest that an increase in the expression of endogenous FPPS could confer at least partial resistance to the pharmacological effect of N-BP drugs such as ZOL in vivo.

Original languageEnglish
Pages (from-to)569-573
Number of pages5
JournalBiochimica et Biophysica Acta
Volume1841
Issue number4
Early online date22 Dec 2013
DOIs
Publication statusPublished - Apr 2014

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Geranyltranstransferase
Protein Prenylation
zoledronic acid
Diphosphonates
HeLa Cells
Up-Regulation
Nitrogen
Prenylation
Monomeric GTP-Binding Proteins
Sterol Regulatory Element Binding Protein 1
Osteitis Deformans
Osteoclasts
Bone Resorption
Cytosol
Lipoproteins
Western Blotting
Pharmacology
Polymerase Chain Reaction
Messenger RNA
Therapeutics

Keywords

  • Bisphosphonate
  • Osteoporosis
  • Farnesyl diphosphate synthase
  • SREBP
  • Prenylation
  • Osteoclast

Cite this

Upregulation of endogenous farnesyl diphosphate synthase overcomes the inhibitory effect of bisphosphonate on protein prenylation in Hela cells. / Das, Subhajit; Edwards, Peter A.; Crockett, Julie C; Rogers, Michael J.

In: Biochimica et Biophysica Acta, Vol. 1841, No. 4, 04.2014, p. 569-573.

Research output: Contribution to journalArticle

Das, Subhajit ; Edwards, Peter A. ; Crockett, Julie C ; Rogers, Michael J. / Upregulation of endogenous farnesyl diphosphate synthase overcomes the inhibitory effect of bisphosphonate on protein prenylation in Hela cells. In: Biochimica et Biophysica Acta. 2014 ; Vol. 1841, No. 4. pp. 569-573.
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abstract = "Nitrogen-containing bisphosphonates (N-BPs) such as zoledronic acid (ZOL) are the gold standard treatment for diseases of excessive bone resorption. N-BPs inactivate osteoclasts via inhibition of farnesyl diphosphate synthase (FPPS), thereby preventing the prenylation of essential small GTPases. Not all patients respond to N-BP therapy to the same extent, and some patients, for example with tumour-associated bone disease or Paget's disease, appear to develop resistance to N-BPs. The extent to which upregulation of FPPS might contribute to these phenomena is not clear. Using quantitative PCR and western blot analysis we show that levels of FPPS mRNA and protein can be upregulated in HeLa cells by culturing in lipoprotein deficient serum (LDS) or by over-expression of SREBP-1a. Upregulated, endogenous FPPS was predominantly localised to the cytosol and did not co-localise with peroxisomal or mitochondrial markers. Upregulation of endogenous FPPS conferred resistance to the inhibitory effect of low concentrations of ZOL on the prenylation of the small GTPase Rap1a. These observations suggest that an increase in the expression of endogenous FPPS could confer at least partial resistance to the pharmacological effect of N-BP drugs such as ZOL in vivo.",
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AU - Rogers, Michael J.

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