Perlmutter Cancer Center, New York University, New York, New York 10016, USA.
Department of Radiation Oncology, University of Michigan Health System, Ann Arbor, Michigan 48109, USA.
Genes Dev. 2021 Feb 1;35(3-4):218-233. doi: 10.1101/gad.344184.120. Epub 2021 Jan 14.
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.
胰腺导管腺癌是一种致命的疾病，其特征为诊断较晚、早期转移倾向和对化疗的耐药性。目前对于导致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症突变相关基因（ATDC）在胰腺癌中过表达，促进肿瘤生长和转移。我们的研究表明，增加的 ATDC 水平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 KEAP1（NRF2 降解的主要调节因子）结合，从而防止 NRF2 的降解，导致 NRF2 依赖性转录程序的激活、细胞内 ROS 的减少和化疗耐药性的增强。我们的发现定义了 ATDC 通过调节 NRF2 活性在调节氧化还原平衡和化疗耐药性中的新作用。
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