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Updated: Oct 20, 2025
A Genetically Engineered Mouse Model of Sporadic Colorectal Cancer
Published on: July 6, 2017
Nrf2 activation does not affect adenoma development in a mouse model of colorectal cancer
Elena V Knatko1, Cecilia Castro2, Maureen Higgins1
1Jacqui Wood Cancer Centre, Division of Cellular Medicine, School of Medicine, University of Dundee, Dundee, Scotland, UK.
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.
Insights
Nuclear factor erythroid 2 p45-related factor 2 (Nrf2) activation does not significantly impact early colorectal adenoma formation. Pharmacological Nrf2 activation is unlikely to affect the early stages of colorectal cancer development.
Area of Science:
- Cellular biology
- Metabolism
- Cancer research
Background:
- Nuclear factor erythroid 2 p45-related factor 2 (Nrf2) and Kelch-like ECH associated protein 1 (Keap1) regulate redox and metabolism.
- Nrf2 activation shows therapeutic benefits but has a dual role in cancer.
- Concerns exist that Nrf2 activators might promote early tumor growth.
Purpose of the Study:
- To investigate the role of Nrf2 in colorectal adenoma development.
- To assess the impact of Nrf2 activation and disruption on early-stage carcinogenesis.
- To evaluate the contribution of Nrf2-mediated metabolic alterations to colorectal tumor formation.
Main Methods:
- Utilized genetic (Gstp-/-: ApcMin/+ mice, Keap1 knockdown) and pharmacological approaches.
- Employed metabolomic analysis to study one-carbon metabolism in colorectal adenomas.
- Assessed colorectal adenoma formation in response to Nrf2 pathway modulation.
Main Results:
- Colorectal adenomas in Gstp-/-: ApcMin/+ mice exhibited altered one-carbon metabolism.
- Genetic Nrf2 activation, but not disruption, modestly enhanced these metabolic alterations.
- Neither genetic nor pharmacological Nrf2 activation or disruption affected adenoma formation.
Conclusions:
- Nrf2-associated metabolic changes have minimal contribution to early colorectal carcinogenesis.
- Pharmacological Nrf2 activation is unlikely to influence the early stages of colorectal cancer development.
- Targeting the Keap1/Nrf2 complex may not promote early-stage colorectal neoplasia.
