Translational reprogramming marks adaptation to asparagine restriction in cancer.
Journal
Nature cell biology
ISSN: 1476-4679
Titre abrégé: Nat Cell Biol
Pays: England
ID NLM: 100890575
Informations de publication
Date de publication:
12 2019
12 2019
Historique:
received:
30
03
2019
accepted:
25
09
2019
pubmed:
20
11
2019
medline:
20
11
2019
entrez:
20
11
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31740775
doi: 10.1038/s41556-019-0415-1
pii: 10.1038/s41556-019-0415-1
pmc: PMC7307327
mid: NIHMS1540628
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1590-1603Subventions
Organisme : NCI NIH HHS
ID : P01 CA128814
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA030199
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA202021
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA197465
Pays : United States
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