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

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.

The Keap1‐Nrf2 System: A Mediator between Oxidative Stress and Aging

“…For instance, minichromosome maintenance protein 3 (MCM3) regulates genome replication and redox homeostasis by competing with Nrf2 for Keap1 [79]. Likewise, other Nrf2 competitors can be potential targets for the development of antiaging and anticancer drugs, such as atypical protein kinase Cι (aPKCι) [80], inhibitor of apoptosis stimulating protein p53 (iASPP) [81], and family with sequence similarity 129, member B (FAM129B) [82]. Strikingly, both p62 accumulation and Keap1 inhibition mediate Nrf2 activation and participate in aging and agingrelated diseases.…”

Dual roles and therapeutic potential of Keap1-Nrf2 pathway in pancreatic cancer: a systematic review

“…In addition to p62, two new Keap1-binding proteins, aPKCι (atypical protein kinase Cι) and PALB2 (partner and localizer of BRCA2) have been reported to inhibit ROS and promote tumor growth and drug resistance by inducing Nrf2 accumulation, nuclear translocation, and activation (Table 1) [41, 42]. Mechanistically, aPKCι and PALB2 share with Nrf2 a highly conserved Keap1-binding motif and compete with Nrf2 for Keap1 binding, protecting Nrf2 from Keap1-mediated protein degradation [41, 42]. Moreover, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) have also been found to regulate the expression of Keap1 in PC [43, 52].…”

Long Noncoding RNA ANPODRT Overexpression Protects Nucleus Pulposus Cells from Oxidative Stress and Apoptosis by Activating Keap1‐Nrf2 Signaling

“…Antioxidant system plays an important role in the occurrence of oxidative stress. The Keap1-Nrf2 signaling cascade is considered a central hub that neutralizes ROS and restores cellular redox balance [ 17 – 20 ]. Under resting conditions, Nrf2 activity is tightly restricted through its interaction with Keap1 in the cytoplasm.…”

“…Keap1 reportedly serves as a substrate scaffold for Cul3-containing E3 ubiquitin ligase, which can induce ubiquitin-proteasome degradation of Nrf2 [ 17 ]. Upon dissociation from Keap1, Nrf2 is translocated into the nucleus, where it initiates the transcription of a battery of antioxidative and cellular defense targets to counteract oxidative stress and modulate redox balance [ 20 ]. In a mouse model of IDD, degenerative changes in IVDs in Nrf2-knockout mice were more severe than those in wild-type mice [ 3 ].…”