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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.
AuthorsS Arkko, H P Zlatev, H Mönkkönen, J Räikkönen, I Benzaïd, P Clézardin, J Mönkkönen, J A Määttä
JournalCancer letters (Cancer Lett) Vol. 357 Issue 1 Pg. 279-285 (Feb 01 2015) ISSN: 1872-7980 [Electronic] Ireland
PMID25444923 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2014 Elsevier Ireland Ltd. All rights reserved.
Chemical References
  • Diphosphonates
  • Imidazoles
  • Receptors, Antigen, T-Cell, gamma-delta
  • T-cell receptor Vdelta2, human
  • T-cell receptor Vgamma9, human
  • Zoledronic Acid
  • Cholesterol
  • Mevalonic Acid
Topics
  • Cell Line, Tumor
  • Cholesterol (deficiency, metabolism)
  • Cytotoxicity, Immunologic (drug effects)
  • Diphosphonates (pharmacology)
  • Humans
  • Imidazoles (pharmacology)
  • Male
  • Mevalonic Acid (metabolism)
  • Prostatic Neoplasms (drug therapy, immunology, metabolism)
  • Receptors, Antigen, T-Cell, gamma-delta (immunology)
  • Signal Transduction (drug effects)
  • T-Lymphocytes (drug effects, immunology)
  • Up-Regulation (drug effects)
  • Zoledronic Acid

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