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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Vydané v:	Nature cell biology Ročník 21; číslo 12; s. 1590 - 1603
Hlavní autori:	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.
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	London Nature Publishing Group UK 01.12.2019 Nature Publishing Group
Predmet:	13 13/1 13/106 13/109 13/2 13/44 13/95 38 45 59 631/337/574 631/67 631/67/2327 631/80/86 64 64/60 96 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
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Shrnutí:	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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 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