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

Knatko et al. examined the importance of Nrf2 activity in the development of colorectal adenomas by performing genetic and pharmacological analyses. The authors found that Keap1 knockdown and Nrf2 activation impacted the metabolism of the non-tumoral colon, but did not affect colorectal adenoma formation in this model. 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(-/-): Apc(Min/+) 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.

Automated summary

The study examined the role of Nrf2 in the development of colorectal adenomas and found that Nrf2 activation had little impact on the early stages of carcinogenesis.