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BMC Cancer
Published in: BMC Cancer 1/2015

Open Access 01-12-2015 | Research article

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

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

Published in: BMC Cancer | Issue 1/2015

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Abstract

Background

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.

Results

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.

Conclusions

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.
Appendix
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Metadata
Title
EIF2A-dependent translational arrest protects leukemia cells from the energetic stress induced by NAMPT inhibition
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
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2015
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-015-1845-1

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