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

作者：Arkko S; Zlatev H P; Monkkonen H; Raikkonen J; Benzaid I; Clezardin R; Monkkonen J; Maatta J A^*

来源：Cancer Letters, 2015, 357(1): 279-285.

DOI：10.1016/j.canlet.2014.11.030

• N-bisphosphonate
• Zoledronic acid
• Phosphoantigen
• Cancer resistance
• Gamma-delta T cell

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 V gamma 9V delta 2 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 V gamma 9V delta 2 T-cell cytotoxicity.
Of the cell lines tested, PC-3 cells were not susceptible to V gamma 9V delta 2 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 V gamma 9V delta 2 T-cell cytotoxicity could be abrogated by upregulation of the mevalonate pathway through cholesterol depletion.