dc.contributor.author | Adam, Isabell | |
dc.contributor.author | Dewi, Dyah L. | |
dc.contributor.author | Mooiweer, Joram | |
dc.contributor.author | Sadik, Ahmed | |
dc.contributor.author | Mohapatra, Soumya R. | |
dc.contributor.author | Berdel, Bianca | |
dc.contributor.author | Keil, Melanie | |
dc.contributor.author | Sonner, Jana K. | |
dc.contributor.author | Thedieck, Kathrin | |
dc.contributor.author | Rose, Adam J. | |
dc.contributor.author | Platten, Michael | |
dc.contributor.author | Heiland, Ines | |
dc.contributor.author | Trump, Saskia | |
dc.contributor.author | Opitz, Christiane A. | |
dc.date.accessioned | 2022-05-03T09:10:43Z | |
dc.date.available | 2022-05-03T09:10:43Z | |
dc.date.issued | 2018-09-05 | |
dc.description.abstract | Tryptophan (Trp) metabolism is an important target in immuno-oncology as it represents a powerful
immunosuppressive mechanism hijacked by tumors for protection against immune destruction.
However, it remains unclear how tumor cells can proliferate while degrading the essential amino acid
Trp. Trp is incorporated into proteins after it is attached to its tRNA by tryptophanyl-tRNA synthestases.
As the tryptophanyl-tRNA synthestases compete for Trp with the Trp-catabolizing enzymes, the balance
between these enzymes will determine whether Trp is used for protein synthesis or is degraded. In
human cancers expression of the Trp-degrading enzymes indoleamine-2,3-dioxygenase-1 (IDO1) and
tryptophan-2,3-dioxygenase (TDO2) was positively associated with the expression of the tryptophanyltRNA synthestase WARS. One mechanism underlying the association between IDO1 and WARS identified
in this study is their joint induction by IFNγ released from tumor-infiltrating T cells. Moreover, we show
here that IDO1- and TDO2-mediated Trp deprivation upregulates WARS expression by activating the
general control non-derepressible-2 (GCN2) kinase, leading to phosphorylation of the eukaryotic translation initiation factor 2α (eIF2α) and induction of activating transcription factor 4 (ATF4). Trp deprivation
induced cytoplasmic WARS expression but did not increase nuclear or extracellular WARS levels. GCN2
protected the cells against the effects of Trp starvation and enabled them to quickly make use of Trp for
proliferation once it was replenished. Computational modeling of Trp metabolism revealed that Trp
deficiency shifted Trp flux towards WARS and protein synthesis. Our data therefore suggest that the
upregulation of WARS via IFNγ and/or GCN2-peIF2α-ATF4 signaling protects Trp-degrading cancer cells
from excessive intracellular Trp depletion. | en_US |
dc.identifier.citation | Adam I, Dewi, Mooiweer, Sadik, Mohapatra, Berdel B, Keil, Sonner, Thedieck, Rose AJ, Platten M, Heiland I, Trump S, Opitz CA. Upregulation of tryptophanyl-tRNA synthethase adapts human cancer cells to nutritional stress caused by tryptophan degradation. Oncoimmunology. 2018;7(12):1-15 | en_US |
dc.identifier.cristinID | FRIDAID 1655218 | |
dc.identifier.doi | 10.1080/2162402X.2018.1486353 | |
dc.identifier.issn | 2162-4011 | |
dc.identifier.issn | 2162-402X | |
dc.identifier.uri | https://hdl.handle.net/10037/24980 | |
dc.language.iso | eng | en_US |
dc.publisher | Taylor & Francis | en_US |
dc.relation.journal | Oncoimmunology | |
dc.rights.accessRights | openAccess | en_US |
dc.rights.holder | Copyright 2018 The Author(s) | en_US |
dc.title | Upregulation of tryptophanyl-tRNA synthethase adapts human cancer cells to nutritional stress caused by tryptophan degradation | en_US |
dc.type.version | publishedVersion | en_US |
dc.type | Journal article | en_US |
dc.type | Tidsskriftartikkel | en_US |
dc.type | Peer reviewed | en_US |