Arginine deprivation enriches lung cancer proteomes with cysteine by inducing arginine-to-cysteine substitutants.

Autor:	Yang C; Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Pataskar A; Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands. Electronic address: a.pataskar@nki.nl., Feng X; Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Montenegro Navarro J; Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Paniagua I; Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Jacobs JJL; Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Zaal EA; Division of Cell Biology, Metabolism & Cancer, Department Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands., Berkers CR; Division of Cell Biology, Metabolism & Cancer, Department Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands., Bleijerveld OB; NKI Proteomics Facility, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Agami R; Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Erasmus MC, Department of Genetics, Rotterdam University, Rotterdam, the Netherlands. Electronic address: r.agami@nki.nl.
Jazyk:	angličtina
Zdroj:	Molecular cell [Mol Cell] 2024 May 16; Vol. 84 (10), pp. 1904-1916.e7.
DOI:	10.1016/j.molcel.2024.04.012
Abstrakt:	Many types of human cancers suppress the expression of argininosuccinate synthase 1 (ASS1), a rate-limiting enzyme for arginine production. Although dependency on exogenous arginine can be harnessed by arginine-deprivation therapies, the impact of ASS1 suppression on the quality of the tumor proteome is unknown. We therefore interrogated proteomes of cancer patients for arginine codon reassignments (substitutants) and surprisingly identified a strong enrichment for cysteine (R>C) in lung tumors specifically. Most R>C events did not coincide with genetically encoded R>C mutations but were likely products of tRNA misalignments. The expression of R>C substitutants was highly associated with oncogenic kelch-like epichlorohydrin (ECH)-associated protein 1 (KEAP1)-pathway mutations and suppressed by intact-KEAP1 in KEAP1-mutated cancer cells. Finally, functional interrogation indicated a key role for R>C substitutants in cell survival to cisplatin, suggesting that regulatory codon reassignments endow cancer cells with more resilience to stress. Thus, we present a mechanism for enriching lung cancer proteomes with cysteines that may affect therapeutic decisions. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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