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

• Published in: Molecular cell Vol. 84; no. 10; pp. 1904 - 1916.e7
• Main Authors: Yang, Chao, Pataskar, Abhijeet, Feng, Xiaodong, Montenegro Navarro, Jasmine, Paniagua, Inés, Jacobs, Jacqueline J.L., Zaal, Esther A., Berkers, Celia R., Bleijerveld, Onno B., Agami, Reuven
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.05.2024; Cell Press
• Subjects: aberrant mRNA translation; amino acid shortage; Arginine - metabolism; arginine deprivation; Argininosuccinate Synthase - genetics; Argininosuccinate Synthase - metabolism; Cell Line, Tumor; Cell Survival - drug effects; chemotherapy; Cisplatin - pharmacology; cysteine; Cysteine - metabolism; ferroptosis; Gene Expression Regulation, Neoplastic; Humans; Kelch-Like ECH-Associated Protein 1 - genetics; Kelch-Like ECH-Associated Protein 1 - metabolism; lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Mutation; Proteome - metabolism; Proteomics - methods; RNA, Transfer - genetics; RNA, Transfer - metabolism; substitutants; lung cancer; arginine deprivation; ferroptosis; cysteine; substitutants; aberrant mRNA translation; chemotherapy; amino acid shortage
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2024.04.012

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. [Display omitted] •Arginine-to-cysteine (R>C) substitutants are enriched in lung cancers with KEAP1 pathway mutations•Arginine deprivation induces R>C substitutants•tRNA misalignment is a proposed mechanism for R>C substitutants in lung cancer•R>C substitutants may enhance resistance to cisplatin treatment Yang, Pataskar, et al. investigated the impact of arginine shortage on aberrant mRNA translation in cancer. They report the enrichment of arginine-to-cysteine substitutants in human lung cancer, link it to a tRNA misalignment mechanism, and connect it to KEAP1 pathway mutations and platinum resistance.