An inhibitor of the Keap1-Nrf2 protein-protein interaction protects NCM460 colonic cells and alleviates experimental colitis

Abstract

Ulcerative colitis (UC) is a chronic relapsing-remitting form of inflammatory bowel disease (IBD) that increases the risk of colorectal cancer, the third most common malignancy in humans. Oxidative stress is a risk factor for the development of UC. The Keap1-Nrf2-ARE pathway is one of the most important defensive mechanisms against oxidative and/or electrophilic stresses. In this study, we identified CPUY192018 as a potent small-molecule inhibitor of the Keap1-Nrf2 PPI, investigated the cyto-protective effects of CPUY192018 on the NCM460 colonic cells and evaluated whether treatment with the inhibitor of the Keap1-Nrf2 PPI exerts protection on an established experimental model of UC induced by dextran sodium sulfate (DSS). Our study clearly demonstrated that CPUY192018 had a cytoprotective effect against DSS in both NCM460 cells and mouse colon via the activation of Nrf2 signaling. These results suggested that activation of Nrf2 by directly inhibiting the Keap1-Nrf2 PPI may be beneficial as a treatment for UC.

Protective Effect of Bruguiera gymnorrhiza (L.) Lam. Fruit on Dextran Sulfate Sodium-Induced Ulcerative Colitis in Mice: Role of Keap1/Nrf2 Pathway and Gut Microbiota

“…Keap1/Nrf2 signaling pathway, an important endogenous antioxidant pathway, serves an essential role in UC (Lu et al, 2016). Nrf2 is an important transcription factor regulating cellular antioxidative stress.…”

“…NF-E2-related factor 2 (Nrf2), a key factor in oxidative stress response of cells regulated by Kelch-like ECH-associated protein 1 (Keap1), moderates the expression of antioxidant proteins and phase II detoxification enzymes (Kitakaze et al, 2019). UC is connected with the Keap1/Nrf2 signaling pathway, and influences Nrf2, Keap1, and Nrf2-related target genes and their expression (Lu et al, 2016). Glutamate-cysteine ligase catalytic subunit (GCLC), glutamate-cysteine ligase modifier subunit (GCLM), h em e o x y ge n a s e-1 ( H O -1 ) a n d NA D ( P ) H q u in on e dehydrogenase 1 (NQO1) belong to the Nrf2 downstream antioxidant enzymes, which are associated with treatment of UC (Song et al, 2019).…”

Nitric Oxide Engages an Anti-inflammatory Feedback Loop Mediated by Peroxiredoxin 5 in Phagocytes

“…These findings are consistent with the notion that the antioxidant response initiated by Keap1 dissociation from Nrf2 reduces inflammatory responses in vivo . In fact, disruption of the Keap1-Nrf2 complex with the electrophilic compound dimethyl fumarate or the protein-protein interaction inhibitor CPUY192018 exhibited protective effects in DSS colitis (Liu et al, 2016; Lu et al, 2016). Our work illuminates the molecular functions of the antioxidant response by defining the Keap1-associated LPS response and identifying Prdx5 as a key component of the antioxidant response required for suppressing TLR signaling in dendritic cells.…”

NRF2 Activation in Cancer: From DNA to Protein

“…Although not assigned to a specific class, the NEDD8-activating enzyme inhibitor (NAE1; hereafter, MLN4924) and the CYP450 inhibitor oltipraz also induce NRF2 activation (107,(125)(126)(127)(128)(129)(130). To date, the CYP450 inhibitor oltipraz and sulforaphane, an isothiocyanate derived from broccoli sprouts, are the only NRF2 inducers to reach phase I and II clinical trials for the prevention of cancer (107,127,128,131,132).…”