Distinct inhibitory effects on mTOR signaling by ethanol and INK128 in diffuse large B-cell lymphoma

Krystyna Mazan-Mamczarz, Raymond J. Peroutka, James J. Steinhardt, Moriah Gidoni, Yongqing Zhang, Elin Lehrmann, Ari L. Landon, Bojie Dai, Simone Houng, Parameswary A. Muniandy, Sol Efroni, Kevin G. Becker, Ronald B. Gartenhaus

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


Background: The mechanistic target of rapamycin, (mTOR) kinase plays a pivotal role in controlling critical cellular growth and survival pathways, and its aberrant induction is implicated in cancer pathogenesis. Therefore, suppression of active mTOR signaling has been of great interest to researchers; several mTOR inhibitors have been discovered to date. Ethanol (EtOH), similar to pharmacologic mTOR inhibitors, has been shown to suppress the mTOR signaling pathway, though in a non-catalytic manner. Despite population studies showing that the consumption of EtOH has a protective effect against hematological malignancies, the mechanisms behind EtOH's modulation of mTOR activity in cells and its downstream consequences are largely unknown. Here we evaluated the effects of EtOH on the mTOR pathway, in comparison to the active-site mTOR inhibitor INK128, and compared translatome analysis of their downstream effects in diffuse large B-cell lymphoma (DLBCL). Results: Treatment of DLBCL cells with EtOH suppressed mTORC1 complex formation while increasing AKT phosphorylation and mTORC2 complex assembly. INK128 completely abrogated AKT phosphorylation without affecting the structure of mTORC1/2 complexes. Accordingly, EtOH less profoundly suppressed cap-dependent translation and global protein synthesis, compared to a remarkable inhibitory effect of INK128 treatment. Importantly, EtOH treatment induced the formation of stress granules, while INK128 suppressed their formation. Microarray analysis of polysomal RNA revealed that although both agents primarily affected cell growth and survival, EtOH and INK128 regulated the synthesis of mostly distinct genes involved in these processes. Though both EtOH and INK128 inhibited cell cycle, proliferation and autophagy, EtOH, in contrast to INK128, did not induce cell apoptosis. Conclusion: Given that EtOH, similar to pharmacologic mTOR inhibitors, inhibits mTOR signaling, we systematically explored the effect of EtOH and INK128 on mTOR signal transduction, components of the mTORC1/2 interaction and their downstream effectors in DLBCL malignancy. We found that EtOH partially inhibits mTOR signaling and protein translation, compared to INK128's complete mTOR inhibition. Translatome analysis of mTOR downstream target genes established that differential inhibition of mTOR by EtOH and INK128 distinctly modulates translation of specific subsets of mRNAs involved in cell growth and survival, leading to differential cellular response and survival.

Original languageEnglish
Article number15
Pages (from-to)15
JournalCell Communication and Signaling
Issue number1
StatePublished - 1 Mar 2015

Bibliographical note

Funding Information:
We are grateful to the University of Maryland Greenebaum Cancer Center Core Flow Cytometry Facility for performing flow cytometric analyses. We also thank our colleague W. H. Wood for providing expert technical assistance. This work was supported in part by the Department of Veterans Affairs (Merit Review Award; R.B.G) and the National institutes of Health (R01AA017972 and R01CA164311; R.B.G). This research was also supported in part by the Intramural Research Program at the National Institute on Aging, National Institutes of Health (Y.Z., E.L., K.G.B).

Publisher Copyright:
© 2015 Mazan-Mamczarz et al.; licensee BioMed Central.


  • EtOH
  • Gene expression
  • INK128
  • MTOR signaling
  • Translation


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