Upregulation of the mevalonate pathway by cholesterol depletion abolishes tolerance to N-bisphosphonate induced V[gamma]9V[delta]2 T cell cytotoxicity in PC-3 prostate cancer cells

• Published in: Cancer letters Vol. 357; no. 1; p. 279
• Main Authors: Arkko, S, Zlatev, HP, Mönkkönen, H, Räikkönen, J, Benzaïd, I, Clézardin, P, Mönkkönen, J, Määttä, JA
• Format: Journal Article
• Language: English
• Published: Clare Elsevier Limited 01.02.2015
• Subjects: Breast cancer; Drug resistance; Immunotherapy; Prostate cancer
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2014.11.030

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.