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Nrf2 activation does not affect adenoma development in a mouse model of colorectal cancer.

Published version
Peer-reviewed

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Type

Article

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Authors

Knatko, Elena V 
Castro, Cecilia 
Higgins, Maureen 
Zhang, Ying 

Abstract

Transcription factor nuclear factor erythroid 2 p45-related factor 2 (Nrf2) and its main negative regulator, Kelch-like ECH associated protein 1 (Keap1), are at the interface between redox and intermediary metabolism. Nrf2 activation is protective in models of human disease and has benefits in clinical trials. Consequently, the Keap1/Nrf2 protein complex is a drug target. However, in cancer Nrf2 plays a dual role, raising concerns that Nrf2 activators may promote growth of early neoplasms. To address this concern, we examined the role of Nrf2 in development of colorectal adenomas by employing genetic, pharmacological, and metabolomic approaches. We found that colorectal adenomas that form in Gstp-/-: ApcMin/+ mice are characterized by altered one-carbon metabolism and that genetic activation, but not disruption of Nrf2, enhances these metabolic alterations. However, this enhancement is modest compared to the magnitude of metabolic differences between tumor and peri-tumoral tissues, suggesting that the metabolic changes conferred by Nrf2 activation may have little contribution to the early stages of carcinogenesis. Indeed, neither genetic (by Keap1 knockdown) nor pharmacological Nrf2 activation, nor its disruption, affected colorectal adenoma formation in this model. We conclude that pharmacological Nrf2 activation is unlikely to impact the early stages of development of colorectal cancer.

Description

Funder: Stony Brook Foundation Reata Pharmaceuticals

Keywords

Adenoma, Animals, Carcinogenesis, Colorectal Neoplasms, Disease Models, Animal, Female, Male, Mice, NF-E2-Related Factor 2

Journal Title

Commun Biol

Conference Name

Journal ISSN

2399-3642
2399-3642

Volume Title

4

Publisher

Springer Science and Business Media LLC
Sponsorship
Cancer Research UK (C20953/A18644)