ATDC binds to KEAP1 to drive NRF2-mediated tumorigenesis and chemoresistance in pancreatic cancer
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jan 14, 2021
- Source ID
- 10.1101/gad.344184.120
Entities
People
- Akash J. Vaidya
- Amit Bhardwaj
- Andrea Zamperone
- Annie Wang
- Costas A Lyssiotis
- Daniel Diolaiti
- Diane M. Simeone
- Ende Zhao
- Erica R. Gumkowski
- Ethan V. Abel
- Gina M. Ney
- Howard C. Crawford
- Huibin Yang
- Igor Dolgalev
- Jiufeng Li
- Lidong Wang
- Marina Pasca di Magliano
- Thales Y. Papagiannakopoulos
- Vinee Purohit
Organizations
- National Cancer Institute
- Pancreatic Cancer Action
- United States Department of Defense