Abstract
BackgroundNicotinamide 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.ResultsWe 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.ConclusionsWe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1845-1) contains supplementary material, which is available to authorized users.
Highlights
Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in Nicotinamide adenine dinucleotide (NAD)+ biosynthesis from nicotinamide, is one of the major factors regulating cancer cells metabolism and is considered a promising target for treating cancer
A marked global protein synthesis inhibition represented an early cellular response associated with the FK866-induced energetic stress and here we show that AMP-activated protein kinase (AMPK)-Eukaryotic translation initiation factor 2A (EIF2A) is a central hub in mediating this effect and is responsible for cell fate decisions
FK866 induces AMPK and EIF2A phosphorylation in Jurkat and primary leukemia cells In view of the strong translation inhibition and considering its energy-sensing activity in controlling translation [37], we investigated in Jurkat cells the impact of FK866 and CHS-828 on the phosphorylation status of AMPK, whose activation has been previously shown to be induced by FK866 in prostate and hepatic cancer cells [23, 24]
Summary
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. Zucal et al BMC Cancer (2015) 15:855 promote cell death in both lymphoid- and myeloid-derived hematological malignancies and its activity clearly resulted from intracellular NAD+ depletion [12,13,14]. The induced NAD+ depletion clearly affects intracellular ATP levels resulting in mitochondrial dysfunction and activation of cell death pathways: reactive oxygen species generation and activation of the apoptotic cascade have both been involved in cell demise in response to NAMPT inhibitors [17]. Translation inhibition is often observed during cell stress [26] and this event often involves a re-programming of translation leading to differential regulation of mRNAs, occurring via alternative mechanisms, aimed at reorganizing cell physiology to respond to the insult
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