PDF(Pubmed)
Abstract：
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.
摘要：
许多类型的人类癌症抑制精氨酸琥珀酸合酶1（ASS1）的表达，精氨酸生产的限速酶。尽管精氨酸剥夺疗法可以利用对外源性精氨酸的依赖性，ASS1抑制对肿瘤蛋白质组质量的影响尚不清楚.因此,我们询问了癌症患者的蛋白质组的精氨酸密码子重新分配(替代),并且令人惊讶地在肺肿瘤中特异性地鉴定了半胱氨酸的强富集(R>C)。大多数R>C事件与遗传编码的R>C突变不一致,但可能是tRNA未对齐的产物。R>C取代子的表达与致癌海带样表氯醇（ECH）相关蛋白1（KEAP1）途径突变高度相关，并在KEAP1突变的癌细胞中被完整的KEAP1抑制。最后,功能询问表明R>C替代物在顺铂的细胞存活中起关键作用，这表明，调节密码子的重新分配赋予癌细胞更多的抗应激能力。因此，我们提出了一种富含半胱氨酸的肺癌蛋白质组可能影响治疗决策的机制.
