aPKCι promotes gallbladder cancer tumorigenesis and gemcitabine resistance by competing with Nrf2 for binding to Keap1

Autor: Yan Liu, Jianming Wang, Li Tian, Jian Zhang, Xiangyu Li, Yun Lu, Wei Yao, Lei Xu, Zhengdong Deng, Tao Yang, Chaoqun Ma
Rok vydání: 2018
Předmět:
0301 basic medicine
IHC
Immunohistochemistry
Nrf2
Nuclear factor erythroid 2-related factor 2
AJCC
American joint committee on cancer
Clinical Biochemistry
Drug resistance
CCK-8
Cell Counting Kit-8
medicine.disease_cause
Biochemistry
Deoxycytidine
Antioxidants
Mice
0302 clinical medicine
GBC
Gallbladder cancer
lcsh:QH301-705.5
Protein Kinase C
CCA
Cholangiocarcinoma
lcsh:R5-920
Kelch-Like ECH-Associated Protein 1
Chemistry
Prognosis
Bcl2
B-cell lymphoma 2
Keap1
Kelch-like ECH-associated protein 1
Cell Transformation
Neoplastic
Gene Knockdown Techniques
Female
Gallbladder Neoplasms
lcsh:Medicine (General)
Chemoresistance
Protein Binding
Signal Transduction
Research Paper
NF-E2-Related Factor 2
Keap1-Nrf2 pathway
ARE
antioxidant response element
Models
Biological
Bile duct cancer
OS
overall survival
03 medical and health sciences
Downregulation and upregulation
Cell Line
Tumor
medicine
Animals
Humans
Protein Interaction Domains and Motifs
Gallbladder cancer
Protein kinase A
aPKC
atypical protein kinase C
Bax
Bcl-2-associated X
Cell growth
Organic Chemistry
Atypical protein kinase Cι
medicine.disease
KEAP1
Gemcitabine
Disease Models
Animal
030104 developmental biology
lcsh:Biology (General)
Drug Resistance
Neoplasm
Cancer research
Co-IP
Co-Immunoprecipitation
Carcinogenesis
Reactive oxygen species
Ect2
Epithelial cell transforming sequence 2
030217 neurology & neurosurgery
ROS
Reactive oxygen species
Zdroj: Redox Biology
Redox Biology, Vol 22, Iss, Pp-(2019)
ISSN: 2213-2317
Popis: 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.
Graphical abstract Image 1
Highlights • aPKCι inhibits ROS in a kinase-independent manner. • aPKCι competes with Nrf2 for binding to Keap1 via a DLL motif. • The aPKCι-Keap1 interaction promotes cell growth and gemcitabine resistance. • Upregulation of aPKCι was linked to poor prognosis in patients with GBC. • aPKCι-Keap1-Nrf2 axis may be a potential therapeutic target for GBC.
Databáze: OpenAIRE
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