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

Elena V Knatko,C Roland Wolf,Maureen Higgins,Colin J Henderson,Albena T Dinkova-Kostova,Ying Zhang,Tadashi Honda,Cecilia Castro,Julian L Griffin

doi:10.1038/s42003-021-02552-w

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.

Highlights

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
Using the Gstp−/−: ApcMin/+ mouse model, in this study we examined the role of Nrf[2] in the development of colorectal adenomas by employing genetic and pharmacological approaches
Because Gstp is involved in xenobiotic metabolism[28] as well as cell signaling, by sequestering c-Jun N-terminal kinase (JNK)[29], we first asked whether deletion of Gstp affects the Nrf2-mediated transcription using the classical Nrf2-target NAD(P)H:quinone oxidoreductase 1 (Nqo1) as a marker, which is expressed in an Nrf2-dependent manner in the mouse colon[30]

Summary

Introduction

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. Mutations in Keap[1] or Nrf[2], which abrogate formation of the Keap1/Nrf[2] protein complex or prevent Nrf[2] ubiquitination, leading to its constitutive activation, occur in several types of human cancer, and are prominent in squamous cell carcinomas of the lung, contributing to tumor growth and resistance to chemoand radiation therapy[19,20]. It was recently shown in the context of non-small cell lung cancer that constitutively active Nrf[2] generates enhancers at gene loci that are not normally regulated following transient activation of Nrf[2] under physiological conditions[21]. We used metabolomics to characterize tumorous and non-tumorous tissue from mice with different levels of Nrf[2]

Methods

Results

Conclusion