Elsevier

Redox Biology

Volume 22, April 2019, 101149
Redox Biology

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

https://doi.org/10.1016/j.redox.2019.101149Get rights and content
Under a Creative Commons license
open access

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.

Abstract

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

Abbreviations

AJCC
American joint committee on cancer
ARE
antioxidant response element
aPKC
atypical protein kinase C
Bax
Bcl-2-associated X
Bcl2
B-cell lymphoma 2
CCA
Cholangiocarcinoma
CCK-8
Cell Counting Kit-8
Co-IP
Co-Immunoprecipitation
Ect2
Epithelial cell transforming sequence 2
GBC
Gallbladder cancer
IHC
Immunohistochemistry
Keap1
Kelch-like ECH-associated protein 1
Nrf2
Nuclear factor erythroid 2-related factor 2
OS
overall survival
ROS
Reactive oxygen species

Cited by (0)