۲- NRF2/KEAP1 Pathway: A Master Regulator of Stress Responses

۳- NRF2/KEAP1 Prooncogenic Activity in Cancer: Causes and Consequences

۴- Therapeutic Strategies for NRF2 Inhibition in Cancer

۵- Future Perspectives and Conclusions

References

Introduction

Living organisms are constantly exposed to multiple challenges and stress sources within the microenvironment and thus have evolved adaptive mechanisms to maintain the homeostasis at the cellular and tissue levels. In this regard, not only fluctuations in the nutrient/oxygen availability but also the presence of electrophiles or xenobiotics can induce alterations in the redox balance and promote cell death by damaging essential macromolecules such as lipids, proteins, and DNA, particularly susceptible to reactive oxygen species (ROS) [1–۴]. Traditionally considered as the master regulator of cytoprotective responses against xenobiotic/electrophilic and oxidative stress [5], the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) was recently found to promote cancer development [6–۱۰], progression [11–۱۴], and therapy resistance [15–۲۲]. Not surprisingly, the renewed interest in NRF2 has fostered many studies directed to elucidate its role in different types of tumors and explore potential therapeutic approaches to prevent or counteract its activation [23–۲۶]. Despite that the dual role of NRF2 as an oncogene or tumor suppressor is still a matter of intense debate [27], in this review, we will mainly focus on its prooncogenic activity while the interested readers are referred to other excellent reviews covering more in detail other aspects [28–۳۱]. We will also briefly discuss risks and benefits derived from the use of negative modulators of NRF2 signaling, with a particular emphasis on repurposing of preexisting drugs and the use of combinatorial treatments aimed at disrupting the redox homeostasis of cancer cells.