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EIF2A-dependent translational arrest protects leukemia cells from the energetic stress induced by NAMPT inhibition

Overview of attention for article published in BMC Cancer, November 2015
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  • High Attention Score compared to outputs of the same age and source (85th percentile)

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1 tweeter
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1 Wikipedia page

Citations

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7 Dimensions

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41 Mendeley
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Title
EIF2A-dependent translational arrest protects leukemia cells from the energetic stress induced by NAMPT inhibition
Published in
BMC Cancer, November 2015
DOI 10.1186/s12885-015-1845-1
Pubmed ID
Authors

Chiara Zucal, Vito G. D’Agostino, Antonio Casini, Barbara Mantelli, Natthakan Thongon, Debora Soncini, Irene Caffa, Michele Cea, Alberto Ballestrero, Alessandro Quattrone, Stefano Indraccolo, Alessio Nencioni, Alessandro Provenzani

Abstract

Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in NAD(+) biosynthesis from nicotinamide, is one of the major factors regulating cancer cells metabolism and is considered a promising target for treating cancer. The prototypical NAMPT inhibitor FK866 effectively lowers NAD(+) levels in cancer cells, reducing the activity of NAD(+)-dependent enzymes, lowering intracellular ATP, and promoting cell death. We show that FK866 induces a translational arrest in leukemia cells through inhibition of MTOR/4EBP1 signaling and of the initiation factors EIF4E and EIF2A. Specifically, treatment with FK866 is shown to induce 5'AMP-activated protein kinase (AMPK) activation, which, together with EIF2A phosphorylation, is responsible for the inhibition of protein synthesis. Notably, such an effect was also observed in patients' derived primary leukemia cells including T-cell Acute Lymphoblastic Leukemia. Jurkat cells in which AMPK or LKB1 expression was silenced or in which a non-phosphorylatable EIF2A mutant was ectopically expressed showed enhanced sensitivity to the NAMPT inhibitor, confirming a key role for the LKB1-AMPK-EIF2A axis in cell fate determination in response to energetic stress via NAD(+) depletion. We identified EIF2A phosphorylation as a novel early molecular event occurring in response to NAMPT inhibition and mediating protein synthesis arrest. In addition, our data suggest that tumors exhibiting an impaired LBK1- AMPK- EIF2A response may be especially susceptible to NAMPT inhibitors and thus become an elective indication for this type of agents.

Twitter Demographics

The data shown below were collected from the profile of 1 tweeter who shared this research output. Click here to find out more about how the information was compiled.

Mendeley readers

The data shown below were compiled from readership statistics for 41 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 41 100%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 12 29%
Researcher 8 20%
Student > Bachelor 4 10%
Student > Postgraduate 3 7%
Professor > Associate Professor 3 7%
Other 8 20%
Unknown 3 7%
Readers by discipline Count As %
Agricultural and Biological Sciences 15 37%
Biochemistry, Genetics and Molecular Biology 10 24%
Medicine and Dentistry 6 15%
Chemistry 3 7%
Immunology and Microbiology 2 5%
Other 2 5%
Unknown 3 7%

Attention Score in Context

This research output has an Altmetric Attention Score of 4. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 29 December 2016.
All research outputs
#2,234,282
of 8,834,354 outputs
Outputs from BMC Cancer
#601
of 3,632 outputs
Outputs of similar age
#71,250
of 248,204 outputs
Outputs of similar age from BMC Cancer
#45
of 313 outputs
Altmetric has tracked 8,834,354 research outputs across all sources so far. This one has received more attention than most of these and is in the 74th percentile.
So far Altmetric has tracked 3,632 research outputs from this source. They receive a mean Attention Score of 3.8. This one has done well, scoring higher than 82% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 248,204 tracked outputs that were published within six weeks on either side of this one in any source. This one has gotten more attention than average, scoring higher than 70% of its contemporaries.
We're also able to compare this research output to 313 others from the same source and published within six weeks on either side of this one. This one has done well, scoring higher than 85% of its contemporaries.