Investigating Nrf2 and Nrf3 as therapeutic targets in cancer

Hobson, Emily (2023) Investigating Nrf2 and Nrf3 as therapeutic targets in cancer. Doctoral thesis, University of East Anglia..

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Abstract

The transcription factor Nrf2 acts as a master regulator of oxidative stress by influencing the expression of genes involved in cytoprotection, redox regulation, and the anti-inflammatory response. While Nrf2 provides a protective effect against carcinogenesis in non-malignant cells, Nrf2 overexpression and aberrant activation in patient tumours contributes to increased tumour growth, metastasis, and chemoresistance. Hence, Nrf2 inhibitors are emerging as potential anti-cancer agents.

In this study, seven Nrf2 inhibitors were compared for the first time for in non-small cell lung cancer (NSCLC) and melanoma cell lines. Among these inhibitors, brusatol and triptolide proved the most efficacious at inhibiting cell proliferation and Nrf2 signalling in both NSCLC and melanoma. Additionally, brusatol, triptolide, and luteolin sensitised cells to the BRAF inhibitor vemurafenib. Triptolide also induced apoptosis and sensitised A549 NSCLC cells to the chemotherapeutic agent, gemcitabine, suggesting that Nrf2 inhibition may be potentially beneficial in Nrf2-overexpressing or chemoresistant NSCLC or melanoma tumours.

Two novel mechanisms of inhibiting Nrf2 were also explored. While triptolide is a potent inhibitor of Nrf2, it possesses several off-target effects. To combat this, we present the first triptolide-peptide conjugate designed to target cancer cells with high Nrf2 and EGFR expression. This study also describes the first peptide-based mimic of the MafG bZIP domain, designed to interrupt the Nrf2/MafG protein-protein interaction. This mimic not only repressed Nrf2-ARE binding, and Nrf2 target gene expression, but also sensitised A549 NSCLC cells to gemcitabine.

The transcription factor Nrf3, which has been implicated in several cancer types, was also explored as a potential therapeutic target in cancer. Herein, we show that Nrf3 is upregulated in patient-derived colorectal tumouroids and is highly expressed in MCF-7 breast, HCT116 colorectal, and MIAPACA2 pancreatic cancer cell lines. Moreover, Nrf3 knockdown significantly repressed migration of MIAPACA2 cells, suggesting that Nrf3 may be a useful therapeutic target in pancreatic cancer.

Item Type:	Thesis (Doctoral)
Faculty \ School:	Faculty of Science > School of Pharmacy
Depositing User:	Nicola Veasy
Date Deposited:	15 Apr 2024 09:41
Last Modified:	15 Apr 2024 09:41
URI:	https://ueaeprints.uea.ac.uk/id/eprint/94904
DOI:

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