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

• Published in: DNA repair Vol. 54; pp. 13 - 21
• Main Authors: Jeddi, Farhad, Soozangar, Narges, Sadeghi, Mohammad Reza, Somi, Mohammad Hossein, Samadi, Nasser
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-06-2017
• Subjects: Animals; Cancer; Chemoresistance; Detoxification; Drug Resistance, Neoplasm; Humans; Keap1; Kelch-Like ECH-Associated Protein 1; Neoplasms - metabolism; Neoplasms - pathology; Neoplasms - prevention & control; NF-E2-Related Factor 2; Nrf2; Oxidative Stress; Signal Transduction; Keap1; Oxidative stress; Nrf2; Detoxification; Chemoresistance; Cancer
• ISSN: 1568-7864; 1568-7856
• DOI: 10.1016/j.dnarep.2017.03.008

•Nrf2 exerts cancer-preventive activity through induction of cytoprotective genes.•Under a deleterious environment, Nrf2 elevates the survival rate of tumor cells.•Nrf2 inhibitors can restore the sensitivity of tumor cells to chemotherapeutic drugs.
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.