ATDC binds to KEAP1 to drive NRF2-mediated tumorigenesis and chemoresistance in pancreatic cancer
Open Access
- 14 January 2021
- journal article
- research article
- Published by Cold Spring Harbor Laboratory in Genes & Development
- Vol. 35 (3-4), 218-233
- https://doi.org/10.1101/gad.344184.120
Abstract
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.Keywords
Funding Information
- Pancreatic Cancer Action Network/AACR Pathway to Leadership (13-70-25-LYSS)
- 2017 AACR
- NextGen
- Transformative Cancer Research (17-20-01-LYSS)
- ACS Research Scholar (RSG-18-186-01)
- Peer Reviewed Cancer Research Program Horizon
- Department of Defense (W81XWH-17-1-0497)
- National Cancer Institute (2R01CA131045, 1R01CA174836)
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