Pancreatic ductal adenocarcinoma is a lethal disease characterized by late diagnosis, propensity for early metastasis and resistance to chemotherapy. Little is known about the mechanisms that drive innate therapeutic resistance in pancreatic cancer. The ataxia-telangiectasia group D-associated gene (ATDC) is overexpressed in pancreatic cancer and promotes tumor growth and metastasis. Our study reveals that increased ATDC levels protect cancer cells from reactive oxygen species (ROS) via stabilization of nuclear factor erythroid 2-related factor 2 (NRF2). Mechanistically, ATDC binds to Kelch-like ECH-associated protein 1 (KEAP1), the principal regulator of NRF2 degradation, and thereby prevents degradation of NRF2 resulting in activation of a NRF2-dependent transcriptional program, reduced intracellular ROS and enhanced chemoresistance. Our findings define a novel role of ATDC in regulating redox balance and chemotherapeutic resistance by modulating NRF2 activity.

中文翻译：

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ATDC 与 KEAP1 结合驱动 NRF2 介导的胰腺癌肿瘤发生和化疗耐药


胰腺导管腺癌是一种致命性疾病，其特点是诊断较晚、易于早期转移和对化疗产生耐药性。人们对胰腺癌固有治疗耐药的机制知之甚少。共济失调毛细血管扩张 D 组相关基因 (ATDC) 在胰腺癌中过度表达，促进肿瘤生长和转移。我们的研究表明，增加的 ATDC 水平可以通过稳定核因子红细胞 2 相关因子 2 (NRF2) 来保护癌细胞免受活性氧 (ROS) 的侵害。从机制上讲，ATDC 与 NRF2 降解的主要调节因子 Kelch 样 ECH 相关蛋白 1 (KEAP1) 结合，从而防止 NRF2 降解，从而激活 NRF2 依赖性转录程序，减少细胞内 ROS 并增强化疗耐药性。我们的研究结果定义了 ATDC 通过调节 NRF2 活性来调节氧化还原平衡和化疗耐药的新作用。