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N6‐isopentenyladenosine arrests tumor cell proliferation by inhibiting farnesyl diphosphate synthase and protein prenylation
Author(s) -
Laezza Chiara,
Notarnicola Maria,
Caruso Maria Gabriella,
Messa Caterina,
Macchia Marco,
Bertini Simone,
Minutolo Filippo,
Portella Giuseppe,
Fiorentino Laura,
Stingo Stefania,
Bifulco Maurizio
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.05-4044lsf
Subject(s) - prenylation , farnesyl pyrophosphate , farnesol , mevalonate pathway , geranylgeraniol , mevalonic acid , chemistry , cell growth , farnesyl diphosphate synthase , biochemistry , cell , terpenoid , atp synthase , enzyme , biology , biosynthesis
The physiological effects of a variety of N6‐substituted adenine and adenosine derivatives called cytokinins have been documented in plants, but information on their occurrence and function in other biological system is limited. Here we investigated the anti‐proliferative effect of N6‐isopentenyladenosine (i 6 A), an adenosine and isoprenoid derivative, in a thyroid cell system, FRTL‐5 wild‐type, and K‐ ras transformed KiMol cells. Addition of i 6 A to FRTL‐5 cells caused a dose‐dependent arrest of the G 0 ‐G 1 cell phase transition associated with a reduction of cells in the S phase that was much more evident in KiMol cells. I 6 A arrested tumor cell proliferation by inhibiting farnesyl diphosphate synthase (FPPS) and protein prenylation. Indeed the addition of farnesol reversed these effects and i 6 A affected protein prenylation, in particular lamin B processing. I 6 A effect was not mediated by the adenosine receptor but was due to a direct modulation of FPPS enzyme activity as a result of its uptake inside the cells. I 6 A inhibited FPPS activity more efficaciously in KiMol cells than in normal FRTL‐5. Moreover, the i 6 A anti‐proliferative effect was evaluated in vivo in a nude mouse xenograft model, where KiMol cells were implanted subcutaneously. Mice treated with i 6 A showed a drastic reduction in tumor volume. Our findings indicate that this isoprenoid end product might be used for antineoplastic therapy, an application emulating that of the lovastatin and/or farnesyltransferase inhibitors.—Laezza, C., Notarnicola, M., Caruso, M. G., Messa, C., Macchia, M., Bertini, S., Minutolo, F., Portella, G., Fiorentino, L., Stingo, S., Bifulco, M. N6‐isopentenyladenosine arrests tumor cell proliferation by inhibiting farnesyl diphosphate synthase and protein prenylation. FASEB J. 20, 412–418 (2006)