title: Upregulation of the mevalonate pathway by cholesterol depletion abolishes tolerance to N-bisphosphonate induced Vγ9Vδ2 T cell cytotoxicity in PC-3 prostate cancer cells.
abstract: Zoledronate (ZOL) inhibits farnesyl pyrophosphate synthase leading to intracellular accumulation of isopentenyl pyrophosphate/triphosphoric acid 1-adenosin-5'-yl ester 3-(3-methylbut-3-enyl) ester (IPP/ApppI). Cytotoxic Vγ9Vδ2 T cells have been shown to recognize IPP/ApppI in breast cancer cells. Further, human breast cancer cells have been shown to differ remarkably in their ZOL treatment induced IPP/ApppI production and responses to that. In this communication we analysed the responsiveness of prostate cancer cells PC-3 and DU-145, Caki-2 renal carcinoma cells and U87MG glioblastoma cells to ZOL treatment, and the subsequent activation of Vγ9Vδ2 T-cell cytotoxicity. Of the cell lines tested, PC-3 cells were not susceptible to Vγ9Vδ2 T-cell cytotoxicity due to low activity of the mevalonate pathway and low amount of IPP formed. However, the resistance of PC-3 cells to Vγ9Vδ2 T-cell cytotoxicity could be abrogated by upregulation of the mevalonate pathway through cholesterol depletion.
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: S
authors.initials: S
authors.lastname: Arkko
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: H P
authors.initials: HP
authors.lastname: Zlatev
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: H
authors.initials: H
authors.lastname: Mönkkönen
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: J
authors.initials: J
authors.lastname: Räikkönen
authors.affiliation: INSERM, UMR 1033, UFR de Médecine Lyon-Est, Université de Lyon, Lyon, France.
authors.forename: I
authors.initials: I
authors.lastname: Benzaïd
authors.affiliation: INSERM, UMR 1033, UFR de Médecine Lyon-Est, Université de Lyon, Lyon, France.
authors.forename: P
authors.initials: P
authors.lastname: Clézardin
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: J
authors.initials: J
authors.lastname: Mönkkönen
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland; Institute of Biomedicine, Department of Cell Biology and Anatomy, University of Turku, Turku, Finland. Electronic address: jormam@uef.fi.
authors.forename: J A
authors.initials: JA
authors.lastname: Määttä
mesh_terms: D045744:Cell Line, Tumor; D002784:Cholesterol / Q000172:deficiency* / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D008798:Mevalonic Acid / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology*; D015854:Up-Regulation / Q000187:drug effects; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D016692:Receptors, Antigen, T-Cell, gamma-delta; C521523:T-cell receptor Vdelta2, human; C521522:T-cell receptor Vgamma9, human; D000077211:Zoledronic Acid; D002784:Cholesterol; D008798:Mevalonic Acid
keywords: Cancer resistance; Gamma-delta T cell; N-bisphosphonate; Phosphoantigen; Zoledronic acid