ATDC binds to KEAP1 to drive NRF2-mediated tumorigenesis and chemoresistance in pancreatic cancer.
ATDC binds to KEAP1 to drive NRF2-mediated tumorigenesis and chemoresistance in pancreatic cancer.
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DOI：
10.1101/gad.344184.120
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发表时间：
2021-02-01
影响因子：
10.5
通讯作者：
Simeone DM
中科院分区：
文献类型：
--
作者：
Purohit V;Wang L;Yang H;Li J;Ney GM;Gumkowski ER;Vaidya AJ;Wang A;Bhardwaj A;Zhao E;Dolgalev I;Zamperone A;Abel EV;Magliano MPD;Crawford HC;Diolaiti D;Papagiannakopoulos TY;Lyssiotis CA;Simeone DM
在这里，Purohit等人研究了驱动胰腺癌先天性治疗耐药的机制。他们表明，增加的共济失调-毛细血管扩张症D组相关基因（ATDC）在胰腺癌中过表达并促进肿瘤生长和转移，通过稳定核因子红细胞2相关因子2（NRF 2）保护癌细胞免受活性氧（ROS）的影响。他们的发现定义了ATDC通过调节NRF 2活性来调节氧化还原平衡和化疗抗性的新作用。胰腺导管腺癌是一种致死性疾病，其特点是诊断晚，易发生早期转移和对化疗耐药。关于胰腺癌先天性治疗耐药的机制知之甚少。共济失调-毛细血管扩张症D组相关基因（ATDC）在胰腺癌中过表达，并促进肿瘤生长和转移。我们的研究表明，增加ATDC水平通过稳定核因子红细胞2相关因子2（NRF 2）保护癌细胞免受活性氧（ROS）的影响。在机制上，ATDC结合Kelch样ECH相关蛋白1（KEAP 1），KEAP 1是NRF 2降解的主要调节因子，从而防止NRF 2降解，导致NRF 2依赖性转录程序的激活，细胞内ROS减少和化学抗性增强。我们的研究结果定义了ATDC通过调节NRF 2活性在调节氧化还原平衡和化疗耐药性中的新作用。
Here, Purohit et al. investigated the mechanisms that drive innate therapeutic resistance in pancreatic cancer. They show that increased ataxia-telangiectasia group D-associated gene (ATDC), which is overexpressed in pancreatic cancer and promotes tumor growth and metastasis, protects cancer cells from reactive oxygen species (ROS) via stabilization of nuclear factor erythroid 2-related factor 2 (NRF2). Their findings define a novel role for ATDC in regulating redox balance and chemotherapeutic resistance by modulating NRF2 activity. 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.
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影响因子：
50.3
作者：
Berger AH;Brooks AN;Wu X;Shrestha Y;Chouinard C;Piccioni F;Bagul M;Kamburov A;Imielinski M;Hogstrom L;Zhu C;Yang X;Pantel S;Sakai R;Watson J;Kaplan N;Campbell JD;Singh S;Root DE;Narayan R;Natoli T;Lahr DL;Tirosh I;Tamayo P;Getz G;Wong B;Doench J;Subramanian A;Golub TR;Meyerson M;Boehm JS
通讯作者：
Boehm JS
影响因子：
11.4
作者：
Bensaad, Karim;Cheung, Eric C.;Vousden, Karen H.
通讯作者：
Vousden, Karen H.
影响因子：
1.2
作者：
Gijsbers, Abril;Nishigaki, Takuya;Sanchez-Puig, Nuria
通讯作者：
Sanchez-Puig, Nuria
影响因子：
7.3
作者：
Davies, Thomas G.;Wixted, William E.;Kerns, Jeffrey K.
通讯作者：
Kerns, Jeffrey K.
影响因子：
15.9
作者：
Collins, Meredith A.;Bednar, Filip;di Magliano, Marina Pasca
通讯作者：
di Magliano, Marina Pasca