Translational reprogramming marks adaptation to asparagine restriction in cancer

While amino acid restriction remains an attractive strategy for cancer therapy, metabolic adaptations limit its effectiveness. Here we demonstrate a role of translational reprogramming in the survival of asparagine-restricted cancer cells. Asparagine limitation in melanoma and pancreatic cancer cell...

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Bibliographic Details
Published in:Nature cell biology Vol. 21; no. 12; pp. 1590 - 1603
Main Authors: Pathria, Gaurav, Lee, Joo Sang, Hasnis, Erez, Tandoc, Kristofferson, Scott, David A., Verma, Sachin, Feng, Yongmei, Larue, Lionel, Sahu, Avinash D., Topisirovic, Ivan, Ruppin, Eytan, Ronai, Ze’ev A.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 01.12.2019
Nature Publishing Group
Subjects:
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Activating transcription factor 4
Adaptation
Amino acids
Asparagine
Aspartate-ammonia ligase
Biomedical and Life Sciences
Cancer
Cancer Research
Care and treatment
Cell Biology
Deprivation
Developmental Biology
Gene expression
Genetic translation
Health aspects
Inhibitors
Initiation factor eIF-4E
Kinases
Life Sciences
Ligases
MAP kinase
Medical prognosis
Melanoma
Pancreatic cancer
Protein-tyrosine kinase receptors
Rapamycin
RNA
Scientific equipment and supplies industry
Sensitizing
Signaling
Stem Cells
TOR protein
Tumors
Tyrosine
France
Canada
United States
ISSN:1465-7392, 1476-4679, 1476-4679
Online Access:Get full text
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Description
Summary:While amino acid restriction remains an attractive strategy for cancer therapy, metabolic adaptations limit its effectiveness. Here we demonstrate a role of translational reprogramming in the survival of asparagine-restricted cancer cells. Asparagine limitation in melanoma and pancreatic cancer cells activates receptor tyrosine kinase–MAPK signalling as part of a feedforward mechanism involving mammalian target of rapamycin complex 1 (mTORC1)-dependent increase in MAPK-interacting kinase 1 (MNK1) and eukaryotic translation initiation factor 4E (eIF4E), resulting in enhanced translation of activating transcription factor 4 ( ATF4 ) mRNA. MAPK inhibition attenuates translational induction of ATF4 and the expression of its target asparagine synthetase (ASNS), sensitizing melanoma and pancreatic tumours to asparagine restriction, reflected in inhibition of their growth. Correspondingly, low ASNS expression is among the top predictors of response to inhibitors of MAPK signalling in patients with melanoma and is associated with favourable prognosis when combined with low MAPK signalling activity. These studies reveal an axis of adaptation to asparagine deprivation and present a rationale for clinical evaluation of MAPK inhibitors in combination with asparagine restriction approaches. Translational reprogramming during asparagine restriction, via activated MAPK signalling and enhanced translation of activating transcription factor 4 ( ATF4 ) mRNA in melanoma and pancreatic cancer cells, provide a survival advantage.
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Author Contributions
GP and ZAR conceived the study; GP, EH, IT, ER, and ZAR designed experiments; GP, EH, KT, SV, and YF performed experiments; GP and DAS conducted metabolic analyses; LL provided valuable reagents; GP, JSL, ADS, EH, KT, ER, and ZAR analyzed data; and GP, ER, IT, and ZAR wrote the manuscript.
ISSN:1465-7392
1476-4679
1476-4679
DOI:10.1038/s41556-019-0415-1