Arginine to Cysteine substitutants in lung cancer enhance survival to chemotherapy

ABSTRACT: Tryptophan and arginine are the two most prominent restrictive amino acids linked to anti-tumor activity. For tryptophan, the induction of indoleamine 2,3-dioxygenase 1 (IDO1) by interferon-gamma (IFNg) secreted by T cells, catabolizes tryptophan to kynurenine to suppress T cell activity. For arginine, tumor cells suppress Argininosuccinate Synthase 1 (ASS1) expression to limit arginine availability for T cell activity (26560030). While tryptophan shortage induces tryptophan to phenylalanine (W>F) substitutants in the proteomes of a variety of tumor types (35264796), whether arginine shortage induces arginine substitutants is unknown. Here, we interrogated the proteomes of cancer patients for arginine substitutions and identified a strong enrichment for cysteine (R>C) specifically in lung tumors. Using a biochemical assay and mass spectrometry, we validated the induction of R>C substitutants by arginine shortage and indicated their link to intracellular high cysteine levels. In the context of lung cancer, R>C events did not overlap with R>C mutations, while a strong correlation with ferroptosis genes and with oncogenic mutations related to the Kelch-like ECH-associated protein 1 (KEAP1) ferroptosis pathway was observed. Indeed, KEAP1 mutations induce intracellular cysteine levels (10.7554/eLife.45572), and the expression of intact KEAP1 in KEAP1-mutated cells suppressed R>C substitutants. We further underpinned tRNA misalignment as the underlying mechanism for R>C events, and, show that boosting R>C serves to enhance resistance to chemotherapy. Thus, our work identified a novel mechanism of enriching proteomes with cysteines, which is exploited by arginine shortage in lung cancer to better endure chemotherapy stress.

INSTRUMENT(S): Orbitrap Fusion, Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Breast Epithelium, Lung Epithelium, Lung Cancer Cell Line, Breast Cancer Cell Line

DISEASE(S): Lung Cancer,Breast Cancer

SUBMITTER: Onno Bleijerveld  

LAB HEAD: Onno B Bleijerveld

PROVIDER: PXD043612 | Pride | 2024-06-16

REPOSITORIES: Pride