Upregulation of the mevalonate pathway by cholesterol depletion abolishes tolerance to N-bisphosphonate induced Vγ9Vδ2 T cell cytotoxicity in PC-3 prostate cancer cells

• Published in: Cancer letters Vol. 357; no. 1; pp. 279 - 285
• Main Authors: Arkko, S, Zlatev, H.P, Mönkkönen, H, Räikkönen, J, Benzaïd, I, Clézardin, P, Mönkkönen, J, Määttä, J.A
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.02.2015
• Subjects: Cancer resistance; Cell Line, Tumor; Cholesterol - deficiency; Cholesterol - metabolism; Cytotoxicity, Immunologic - drug effects; Diphosphonates - pharmacology; Gamma-delta T cell; Hematology, Oncology and Palliative Medicine; Humans; Imidazoles - pharmacology; Male; Mevalonic Acid - metabolism; N-bisphosphonate; Phosphoantigen; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - immunology; Prostatic Neoplasms - metabolism; Receptors, Antigen, T-Cell, gamma-delta - immunology; Signal Transduction - drug effects; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Up-Regulation - drug effects; Zoledronic acid; Rap1A; methyl-beta-cyclodextrin; multi resistance-associated protein-1; 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; IPP; N-BP; MRP-1; MTT; geranylgraniol; HMGR; nitrogen containing bisphosphonate; ApppI; zoledronic acid; GGOH; multi drug resistance-1 (P-glycoprotein); 3-hydroxy-3-methylglutaryl coenzyme A reductase; FOH; high pressure liquid chromatography–electrospray ionization mass spectrometry; isopentenyl pyrophosphate; MDR-1; unprenylated Rap1A; unRap1A; member of Ras oncogene family; enhanced chemiluminescence; FPPS; ECL; Phosphoantigen; triphosphoric acid 1-adenosin-5′-yl ester 3-(3-methylbut-3-enyl) ester; ZOL; Gamma-delta T cell; farnesol; Cancer resistance; farnesyl pyrophosphate synthase; HPLC–ESI-MS; mβCD; N-bisphosphonate; Zoledronic acid
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2014.11.030

Highlights • PC-3 prostate cancer cells treated with zoledronate were shown to be resistant to Vγ9Vδ2 T cell cytotoxicity. • Resistance was attributed to the low activity of the mevalonate pathway in these cells. • PC-3 cells could be rendered susceptible to Vγ9Vδ2 T cell mediated cytotoxicity by activating the mevalonate pathway. • Cholesterol depletion together with ZOL treatment led to high accumulation of IPP, which was recognized by Vγ9Vδ2 T cells.