Perillyl alcohol and genistein differentially regulate PKB/Akt and 4E-BP1 phosphorylation as well as eIF4E/eIF4G interactions in human tumor cells

Previously we demonstrated that secondary products of plant mevalonate metabolism called isoprenoids attenuate 3-hydroxy-3-methylglutaryl coenzyme A reductase mRNA translational efficiency and cause tumor cell death. Here we compared effects of “pure” isoprenoids (perillyl alcohol and γ-tocotrienol)...

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Bibliographic Details
Published in:Archives of biochemistry and biophysics 2007-09, Vol.465 (1), p.266-273
Main Authors: Peffley, Dennis M., Sharma, Catherine, Hentosh, Patricia, Buechler, Robbie D.
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - metabolism
Cell Line, Tumor
Dose-Response Relationship, Drug
eIF4F
Eukaryotic Initiation Factor-4E - metabolism
Eukaryotic Initiation Factor-4G - metabolism
Gene Expression Regulation, Neoplastic - drug effects
Genistein - administration & dosage
Humans
Isoflavones
Isoprenoids
m7GpppX cap binding complex
Monoterpenes - administration & dosage
mTOR signaling
Neoplasms - metabolism
Phosphoproteins - metabolism
Phosphorylation - drug effects
Protein translation
Proto-Oncogene Proteins c-akt - metabolism
Signal Transduction - drug effects
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Summary:Previously we demonstrated that secondary products of plant mevalonate metabolism called isoprenoids attenuate 3-hydroxy-3-methylglutaryl coenzyme A reductase mRNA translational efficiency and cause tumor cell death. Here we compared effects of “pure” isoprenoids (perillyl alcohol and γ-tocotrienol) and a “mixed” isoprenoid—genistein—on the PKB/Akt/mTOR pathway that controls mRNA translation and m 7GpppX eIF4F cap binding complex formation. Effects were cell- and isoprenoid-specific. Perillyl alcohol and genistein suppressed 4E-BP1(Ser65) phosphorylation in prostate tumor cell lines, DU145 and PC-3, and in Caco2 adenocarcinoma cells. Suppressive effects were similar to or greater than that observed with a PI3 kinase inhibitor or rapamycin, an mTOR inhibitor. 4E-BP1(Thr37) phosphorylation was reduced by perillyl alcohol and genistein in DU145, but not in PC-3. Conversely, perillyl alcohol but not genistein decreased 4E-BP1(Thr37) phosphorylation in Caco2. PKB/Akt activation via Ser473 phosphorylation was enhanced in DU145 by perillyl alcohol and in PC-3 by γ-tocotrienol, but was suppressed by genistein. Importantly, perillyl alcohol disrupted interactions between eIF4E and eIF4G, key components of eIF4F (m 7GpppX) cap binding complex. These results demonstrate that “pure” isoprenoids and genistein differentially impact cap-dependent translation in tumor cell lines.
ISSN:0003-9861
1096-0384
DOI:10.1016/j.abb.2007.05.022