Protein S-palmitoylation is a powerful post-translational modification that regulates protein trafficking, localization, turnover, and signal transduction. Palmitoylation controls several important cellular processes, and, if dysregulated, can lead to cancer, cardiovascular disease, and neurological disorders. The role of protein palmitoylation in mediating resistance to systemic cisplatin-based chemotherapies in cancer is currently unknown. This is of particular interest because cisplatin is currently the gold standard of treatment for bladder cancer (BC), and there are no feasible options after resistance is acquired. Using unbiased global proteomic profiling of purified S-palmitoylated peptides combined with intensive bioinformatics analyses, we identified 506 candidate palmitoylated proteins significantly enriched in cisplatin-resistant BC cells. One of these proteins included PD-L1, which is highly palmitoylated in resistant cells. Pharmacological inhibition of fatty acid synthase (FASN) suppressed PD-L1 palmitoylation and expression, which suggests the potential use of FASN-PD-L1-targeted therapeutic strategies in BC patients. Taken together, these results highlight the role of protein palmitoylation in mediating BC chemoresistance.

中文翻译：

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S-棕榈酰化作为与膀胱癌顺铂耐药相关的蛋白质的功能调节剂。

蛋白质S -棕榈酰化是一种强大的翻译后修饰，可调节蛋白质运输、定位、转换和信号转导。棕榈酰化控制着几个重要的细胞过程，如果失调，会导致癌症、心血管疾病和神经系统疾病。蛋白质棕榈酰化在介导癌症对全身性顺铂化疗耐药中的作用目前尚不清楚。这特别令人感兴趣，因为顺铂是目前治疗膀胱癌 (BC) 的金标准，并且在获得耐药性后没有可行的选择。使用纯化S 的无偏全局蛋白质组学分析-棕榈酰化肽结合密集的生物信息学分析，我们确定了 506 种候选棕榈酰化蛋白，这些蛋白在顺铂耐药性 BC 细胞中显着富集。其中一种蛋白质包括 PD-L1，它在抗性细胞中高度棕榈酰化。脂肪酸合酶 (FASN) 的药理学抑制抑制了 PD-L1 棕榈酰化和表达，这表明 FASN-PD-L1 靶向治疗策略在 BC 患者中的潜在用途。总之，这些结果突出了蛋白质棕榈酰化在介导 BC 化学抗性中的作用。