文章目录

sult1a1依赖性烷基化是肝癌的一种谱系依赖性易感性

原文发布日期：2023-03-13

英文摘要：

摘要翻译：

原文链接：

文章：

sult1a1依赖性烷基化是肝癌的一种谱系依赖性易感性

SULT1A1-dependent sulfonation of alkylators is a lineage-dependent vulnerability of liver cancers

原文发布日期：2023-03-13

英文摘要：

Adult liver malignancies, including intrahepatic cholangiocarcinoma and hepatocellular carcinoma, are the second leading cause of cancer-related deaths worldwide. Most individuals are treated with either combination chemotherapy or immunotherapy, respectively, without specific biomarkers for selection. Here using high-throughput screens, proteomics and in vitro resistance models, we identify the small molecule YC-1 as selectively active against a defined subset of cell lines derived from both liver cancer types. We demonstrate that selectivity is determined by expression of the liver-resident cytosolic sulfotransferase enzyme SULT1A1, which sulfonates YC-1. Sulfonation stimulates covalent binding of YC-1 to lysine residues in protein targets, enriching for RNA-binding factors. Computational analysis defined a wider group of structurally related SULT1A1-activated small molecules with distinct target profiles, which together constitute an untapped small-molecule class. These studies provide a foundation for preclinical development of these agents and point to the broader potential of exploiting SULT1A1 activity for selective targeting strategies.

摘要翻译：

成年肝癌，包括胆管状细胞癌和肝细胞癌，是全球导致癌症死亡的第二种主要原因。大多数患者接受的是分别采用联合化疗或免疫疗法治疗，而没有针对特定患者的筛选标志。在这里，我们通过高通量筛选、蛋白质组学以及体外抗性模型研究，识别出一种小分子药物YC-1对两种类型的肝癌细胞系中的特定亚群具有选择性作用。研究表明，选择作用与肝脏固着的胞液硫代转移酶家族成员SULT1A1表达水平增加有关。SULT1A1催化YC-1脱硫，使得YC-1通过与蛋白质靶标的共价结合，并促进RNA结合因子的富集而得以在体外实现高选择性作用。通过计算分析，我们定义了一组结构上相关的、由SULT1A1激活的小分子药物，这些药物各自具有独特的靶点特征。这些小分子药物共同构成了一个尚未被探索的小分子药物类别。这些研究为这些药物的临床前研究阶段的发展奠定了基础，并将SULT1A1活性在选择性靶向治疗中的潜在应用引向更广的领域。