title: Upregulation of endogenous farnesyl diphosphate synthase overcomes the inhibitory effect of bisphosphonate on protein prenylation in Hela cells.
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.
authors.affiliation: Musculoskeletal Research Programme, Division of Applied Medicine, School of Medicine and Dentistry, University of Aberdeen, Aberdeen, UK.
authors.forename: Subhajit
authors.initials: S
authors.lastname: Das
authors.affiliation: School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Edwards
authors.affiliation: Musculoskeletal Research Programme, Division of Applied Medicine, School of Medicine and Dentistry, University of Aberdeen, Aberdeen, UK. Electronic address: j.c.crockett@abdn.ac.uk.
authors.forename: Julie C
authors.initials: JC
authors.lastname: Crockett
authors.affiliation: Bone Biology Division, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia; St. Vincent's Clinical School, University of New South Wales, Australia.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rogers
mesh_terms: D001862:Bone Resorption / Q000235:genetics* / Q000473:pathology; D004164:Diphosphonates / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D051228:Geranyltranstransferase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism; D017368:Protein Prenylation / Q000187:drug effects*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000096:biosynthesis; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D051780:Sterol Regulatory Element Binding Protein 1; D000077211:Zoledronic Acid; D051228:Geranyltranstransferase
keywords: Bisphosphonate; Farnesyl diphosphate synthase; Osteoclast; Osteoporosis; Prenylation; SREBP