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eIF4E-Overexpression imparts perillyl alcohol and rapamycin-mediated regulation of telomerase reverse transcriptase

Tabetha Sundin1, Dennis Peffley1, Patricia Hentosh1

  • 1Department of Biomedical Sciences, University of South Carolina School of Medicine-Greenville, Greenville, SC 29605.

Experimental Cell Research
|June 11, 2013
PubMed

Insights

Overexpressing eukaryotic initiation factor 4E (eIF4E) in cells enables perillyl alcohol (POH) and rapamycin to inhibit telomerase activity and telomerase reverse transcriptase (TERT) protein. This highlights eIF4E

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • Translation initiation is regulated by eukaryotic initiation factor 4E (eIF4E) via PI3K-Akt-mTOR signaling.
  • Perillyl alcohol (POH) and rapamycin inhibit cap-dependent translation and affect telomerase activity in cancer cells with elevated eIF4E.

Purpose of the Study:

  • To investigate the specific role of eIF4E in the regulation of telomerase activity by POH and rapamycin.
  • To elucidate the mechanisms underlying eIF4E-mediated control of telomerase in response to these compounds.

Main Methods:

  • Utilized immortalized Chinese hamster ovary (CHO) control cells and CHO cells overexpressing eIF4E (rb4E).
  • Assessed telomerase activity, telomerase reverse transcriptase (TERT) mRNA, and TERT protein levels.
  • Monitored signaling pathway components including S6K, Akt, and 4E-BP1.

Main Results:

  • Despite higher eIF4E levels, basal telomerase activity, TERT mRNA, and TERT protein were similar in control and rb4E cells.
  • POH and rapamycin treatment attenuated telomerase activity and TERT protein in rb4E cells, but not in control cells.
  • These inhibitory effects in rb4E cells occurred without changes in TERT mRNA, suggesting translational or post-translational regulation.
  • Signaling pathway components (S6K, Akt, 4E-BP1) were modulated by mTOR mediators only in eIF4E-overexpressing cells.

Conclusions:

  • eIF4E overexpression is critical for mediating the inhibitory effects of POH and rapamycin on telomerase and TERT protein.
  • These findings demonstrate that eIF4E overexpression alters cellular protein synthesis and gene regulation in response to these agents.
  • The study underscores the importance of eIF4E in linking signaling pathways to telomerase regulation.
Keywords:
3-[(3-Cholamidopropyl)dimethylammonio]-l-propanesulfonic acid3-hydroxy-3-methylglutaryl-CoA reductase4E T4E-BP14E-binding protein 1CHAPSCHOChinese hamster ovaryEtOHHMG-CoA reductaseOncogene addictionOncogenic shockP-bodiesPI3KPI3K-Akt-mTOR pathwayPOHPVDFRTQ-TRAPRapaS6KTERTTelomerase activityTelomerase reverse transcriptaseUTReIF4eIF4E-overexpressioneIF4E-transporterethanoleukaryotic initiation factor 4mTORmechanistic target of rapamycinp70 S6 kinaseperillyl alcoholphosphoinositide 3-kinasepolyvinylidene fluorideprocessing-bodiesrapamycinreal-time quantitative telomerase repeat amplification protocoltelomerase reverse transcriptaseuntranslated region

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