Contradictory roles of Nrf2/Keap1 signaling pathway in cancer prevention/promotion and chemoresistance

Abstract

NF-E2-related factor 2 (Nrf2) protein is a cytosolic transcription factor that regulates antioxidant and stress related enzymes. Kelch-like ECH-associated protein 1 (Keap1) binds Nrf2 and accelerates ubiquitination and proteasome-dependent degradation of Nrf2. Nrf2 modifies the sensitivity of the cell environment to electrophiles and oxidants by inducing the transcriptional activation of more than 100 detoxification and cytoprotective genes. Prior investigations have found documentary evidence indicating that temporary activation of Nrf2 by pharmaceutical inducers plays a protective role against cancer initiation in normal cells. The impact of Nrf2/Keap1 pathway in development of tumorigenesis and drug resistance has also been well documented. Inhibition of the permanent Nrf2 activation, especially in combination with chemotherapeutics against cancer, may be considered as an important strategy to inhibit tumor growth and overcome chemoresistance. Here, we review the importance of Nrf2-Keap1 pathway in the prevention or promotion of cancer, and resistance mechanisms to chemotherapeutic agents.