aPKCι promotes gallbladder cancer tumorigenesis and gemcitabine resistance by competing with Nrf2 for binding to Keap1
Li Tian,
Yun Lu,
Tao Yang,
Zhengdong Deng,
Lei Xu,
Wei Yao,
Chaoqun Ma,
Xiangyu Li,
Jian Zhang,
Yan Liu,
Jianming Wang
Affiliations
Li Tian
Department of Biliary and Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
Yun Lu
Department of Biliary and Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
Tao Yang
Department of Biliary and Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
Zhengdong Deng
Department of Biliary and Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
Lei Xu
Department of Biliary and Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
Wei Yao
Department of Oncology, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
Chaoqun Ma
Department of Biliary and Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
Xiangyu Li
Department of Biliary and Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
Jian Zhang
Department of Biliary and Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
Yan Liu
Department of Geriatrics, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
Jianming Wang
Department of Biliary and Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Corresponding author.
Gallbladder cancer (GBC) is a highly malignant bile duct cancer with poor prognosis characterized by its insensitivity to chemotherapy. Emerging evidence indicates that cytoprotective antioxidation is involved in drug resistance of various cancers; however, the underlying molecular mechanisms remain obscure. Here, we demonstrated that atypical protein kinase Cι (aPKCι) mediated reactive oxygen species (ROS) inhibition in a kinase-independent manner, which played a crucial role in tumorigenesis and chemoresistance. Mechanistically, we found that aPKCι facilitated nuclear factor erythroid 2-related factor 2 (Nrf2) accumulation, nuclear translocation and activated its target genes by competing with Nrf2 for binding to Kelch-like ECH-associated protein 1 (Keap1) through a highly conserved DLL motif. In addition, the aPKCι-Keap1 interaction was required for antioxidant effect, cell growth and gemcitabine resistance in GBC. Importantly, we further confirmed that aPKCι was frequently upregulated and correlated with poor prognosis in patients with GBC. Collectively, our findings suggested that aPKCι positively modulated the Keap1-Nrf2 pathway to enhance GBC growth and gemcitabine resistance, implying that the aPKCι-Keap1-Nrf2 axis may be a potential approach to overcome the drug resistance for the treatment of GBC. Keywords: Gallbladder cancer, Atypical protein kinase Cι, Chemoresistance, Reactive oxygen species, Keap1-Nrf2 pathway
