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

Cell Communication and Signaling

Research

Kevin G Becker¹  Yongqing Zhang¹  Elin Lehrmann¹  Ari L Landon²  Raymond J Peroutka²  Krystyna Mazan-Mamczarz²  James J Steinhardt²  Simone Houng²  Parameswary A Muniandy²  Bojie Dai²  Ronald B Gartenhaus³  Moriah Gidoni⁴  Sol Efroni⁴ 

[1] Gene Expression and Genomics Unit, National Institute of Aging, National Institutes of Health, 21224, Baltimore, MD, USA;Marlene & Stewart Greenebaum Cancer Center, Department of Medicine, University of Maryland, 21201, Baltimore, MA, USA;Marlene & Stewart Greenebaum Cancer Center, Department of Medicine, University of Maryland, 21201, Baltimore, MA, USA;Veterans Administration Medical Center, 21201, Baltimore, MD, USA;The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, 5290002, Ramat-Gan, Israel;

关键词: mTOR signaling;    Translation;    EtOH;    INK128;    DLBCL;    Gene expression;   

DOI  :  10.1186/s12964-015-0091-0

 received in 2014-11-20, accepted in 2015-02-04,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundThe 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).ResultsTreatment 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.ConclusionGiven 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.

【 授权许可】

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© Mazan-Mamczarz et al.; licensee BioMed Central. 2015. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.