The Nrf2-Keap1-ARE Signaling Pathway: The Regulation and Dual Function of Nrf2 in Cancer

The NF-E2-related factor-2 (Nrf2) is a transcription factor that is ubiquitously expressed at low levels in all human organs. As Nrf2 regulates a major cellular defense mechanism, tight regulation is crucial to maintain cellular homeostasis. Activation of this pathway is important in preventing human diseases, such as cancer, neurodegenerative disease, cardiovascular diseases, ischemia, diabetes, pulmonary fibrosis, and inflammatory diseases. Conversely, high constitutive levels of Nrf2 occur in many tumors or cancer cell lines. Moreover, overexpression of Nrf2 in cancer cells protects them from the cytotoxic effects of anticancer therapies, resulting in chemo-and/or radioresistance. Therefore, understanding Nrf2 regulation and identifying Nrf2 activators or inhibitors for disease prevention or as sensitizing agents during cancer therapy, respectively, will have a significant impact on human health. The growing interest in Nrf2 is reflected by an exponentially increasing number of annual publications on this topic. The present forum provides a comprehensive review on research conducted since the initial discovery of the Nrf2-Keap1 pathway in 1999, provides readers with insight into contemporary research in this field, and assesses current known biological functions of this pathway. Additionally, the forum will serve as an important resource for both graduate students and active researchers who are interested in the Nrf2 field. Antioxid. Redox Signal. 13, 1623-1626.