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

Abstract

Pancreatic cancer (PC) is one of the most fatal diseases with a very high rate of metastasis and low rate of survival. Despite the advances in understanding this devastating disease, PC still accounts for 3% of all cancers and causes almost 7% of death of cancer patients. Recent studies have demonstrated that the transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) and its key negative regulator Kelch-like ECH-associated protein 1 (Keap1) are dysregulated in PC and the Keap1-Nrf2 pathway is an emerging target for PC prevention and therapy. Indeed, Nrf2 plays an either tumor-suppressive or promoting function in PC, which depends on the developmental stages of the disease and the cellular context. Several natural-product Nrf2 activators have been developed to prevent pancreatic carcinogenesis, while the Nrf2 inhibitors have been examined for their efficacy in inhibiting PC growth and metastasis and reversing chemoresistance. However, further preclinical and clinical studies for determining the effectiveness and safety of targeting the Keap1-Nrf2 pathway for PC prevention and therapy are warranted. In this review, we comprehensively discuss the dual roles of the Keap1-Nrf2 signaling pathway in PC as well as the current targeting strategies and known activators and inhibitors of Nrf2. We also propose new strategies that may be used to address the current issues and develop more specific and more effective Nrf2 activator/inhibitors for PC prevention and therapy.

Keywords: Keap1; Nrf2; Pancreatic cancer; Prevention and therapy; Small molecule activators and inhibitors; Tumor-suppressive and promoting roles.

Fig. 1

The dual roles of Keap1-Nrf2 signaling pathway in pancreatic cancer. In normal cells, Nrf2 is temporarily activated when exposed to electrophiles and ROS and activates the transcription of genes that increase the capabilities of detoxification, antioxidant, and immune surveillance, preventing chemical-induced carcinogenesis. In Nrf2-addicted cancer cells, Keap1 is deleted or expressed at a very low level. Nrf2 is overexpressed and constitutively activated and promotes cancer growth and metastasis by regulating its downstream target genes

Fig. 2

Schematic structures of Keap1 and Nrf2. a Nrf2 comprises seven Nrf2-ECH homology (Neh) domains, Neh1-Neh7. Among these domains, Neh2 and Neh6 are important for binding with the negative regulators Keap1 and β-TrCP, respectively, consequently causing Nrf2 ubiquitination and degradation. Neh1 contains a cap ‘n’ collar (CNC) basic-region leucine zipper (bZIP) domain that is important for interacting with small MAF (sMAF) proteins and DNA. Neh1 also holds a nuclear localization signal (NLS) which is required for the nuclear translocation of Nrf2. Neh3, Neh4, and Neh5 domains are necessary for transactivation. Neh7 is important for binding with an Nrf2 repressor, the retinoic X receptor α (RXRα). b Keap1 comprises an N-terminal region (NTR), a broad complex, Tramtrack and Bric-à-Brac (BTB) domain, an intervening region (IVR), six Kelch repeats, and a C-terminal region (CTR). Among these domains, BTB domain is responsible for the homodimerization of Keap1 and the binding with Cullin3 (Cul3) E3 ligase. BTB also harbors cysteine residues, which are reactive to electrophiles and reactive oxygen species (ROS). Kelch repeats contain binding sites that are important for interacting with Nrf2, p62, and other E/STGE proteins. IVR contains a nuclear export signal (NES), which regulates the cytoplasmic localization of Keap1

Fig. 3

The Keap1-Nrf2 signaling pathway. Under normal physiological conditions, the Nrf2 protein level is tightly controlled by Keap1. Keap1 dimerizes through the N-terminal BTB domain and forms E3 ubiquitin ligase complexes with Cullin3 (Cul3) and Ring box protein-1 (RBX1), then promoting Nrf2 ubiquitination and degradation. Nrf2 is also negatively regulated by the E3 ubiquitin ligase complexes, the β-TrCP-SKP1-Cullin1 (Cul1)-RBX1 and HRD1. When cells are exposed to electrophiles or ROS or under endoplasmic reticulum (ER) stress, the Nrf2 protein level is increased. Nrf2 then translocates into the nucleus, forms heterodimers with sMAF proteins, binds to the antioxidant response elements (AREs), and then activates the transcription of ARE-driven genes. p62 also interacts with the Nrf2-binding site on Keap1 and releases Nrf2 from Keap1-mediated protein degradation

Fig. 4

Targeting Keap1-Nrf2 signaling pathway for pancreatic cancer prevention and therapy. Several strategies have been proposed to target the Nrf2 signaling pathway in human pancreatic cancer: (1) modulating Nrf2 expression at the transcriptional level, (2) modulating the Nrf2 activity by targeting its upstream activators and stabilizers, (3) affecting the nuclear translocation of Nrf2, (4) targeting the Keap1-Nrf2 binding for modulating Nrf2 protein stability, (5) targeting the β-TrCP-Nrf2 binding or the HRD1-Nrf2 binding and modulating Nrf2 ubiquitination and degradation, (6) modulating the binding of Nrf2 with its co-activators in the nucleus, and (7) modulating the binding of Nrf2 with its downstream target genes. Many small-molecule Nrf2 activators and inhibitors have been discovered and shown efficacy in pancreatic cancer cells in vitro and in vivo