title: eIF4E-Overexpression imparts perillyl alcohol and rapamycin-mediated regulation of telomerase reverse transcriptase.
abstract: Translation is mediated partly by regulation of free eukaryotic initiation factor 4E (eIF4E) levels through PI3K-Akt-mTOR signaling. Cancer cells treated with the plant-derived perillyl alcohol (POH) or the mechanistic target of rapamycin (mTOR) inhibitor rapamycin dephosphorylate eIF4E-binding protein (4E-BP1) and attenuate cap-dependent translation. We previously showed in cancer cell lines with elevated eIF4E that POH and rapamycin regulate telomerase activity through this pathway. Here, immortalized Chinese hamster ovary (CHO) control cells and CHO cells with forced eIF4E expression (rb4E) were used to elucidate eIF4E's role in telomerase regulation by POH and rapamycin. Despite 5-fold higher eIF4E amounts in rb4E, telomerase activity, telomerase reverse transcriptase (TERT) mRNA, and TERT protein were nearly equivalent in control and rb4E cells. In control cells, telomerase activity, TERT mRNA and protein levels were unaffected by either compound. In contrast, telomerase activity and TERT protein were both attenuated by either agent in rb4E cells, but without corresponding TERT mRNA decreases indicating a translational/post-translational process. S6K, Akt, and 4E-BP1 were modulated by mTOR mediators only in the presence of increased eIF4E. Thus, eIF4E-overexpression in rb4E cells enables inhibitory effects of POH and rapamycin on telomerase and TERT protein. Importantly, eIF4E-overexpression modifies cellular protein synthetic processes and gene regulation.
authors.affiliation: Department of Biomedical Sciences, University of South Carolina School of Medicine-Greenville, Greenville, SC 29605. Electronic address: trsundin@sentara.com.
authors.forename: Tabetha
authors.initials: T
authors.lastname: Sundin
authors.affiliation: Department of Biomedical Sciences, University of South Carolina School of Medicine-Greenville, Greenville, SC 29605. Electronic address: PEFFLEY@greenvillemed.sc.edu.
authors.forename: Dennis
authors.initials: D
authors.lastname: Peffley
authors.affiliation: Department of Biomedical Sciences, University of South Carolina School of Medicine-Greenville, Greenville, SC 29605. Electronic address: phentosh@odu.edu.
authors.forename: Patricia
authors.initials: P
authors.lastname: Hentosh
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004789:Enzyme Activation / Q000187:drug effects; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D039821:Monoterpenes / Q000494:pharmacology*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D039561:Eukaryotic Initiation Factor-4E; D039821:Monoterpenes; C032208:perillyl alcohol; D051058:Oncogene Protein v-akt; D019893:Ribosomal Protein S6 Kinases; D019098:Telomerase; D020123:Sirolimus
keywords: 3-[(3-Cholamidopropyl)dimethylammonio]-l-propanesulfonic acid; 3-hydroxy-3-methylglutaryl-CoA reductase; 4E T; 4E-BP1; 4E-binding protein 1; CHAPS; CHO; Chinese hamster ovary; EtOH; HMG-CoA reductase; Oncogene addiction; Oncogenic shock; P-bodies; PI3K; PI3K-Akt-mTOR pathway; POH; PVDF; RTQ-TRAP; Rapa; S6K; TERT; Telomerase activity; Telomerase reverse transcriptase; UTR; eIF4; eIF4E-overexpression; eIF4E-transporter; ethanol; eukaryotic initiation factor 4; mTOR; mechanistic target of rapamycin; p70 S6 kinase; perillyl alcohol; phosphoinositide 3-kinase; polyvinylidene fluoride; processing-bodies; rapamycin; real-time quantitative telomerase repeat amplification protocol; telomerase reverse transcriptase; untranslated region