The emerging role of the Nrf2–Keap1 signaling pathway in cancer

By Melba C. Jaramillo, Donna D. Zhang. Genes & Development, 2013

1,271 citations recorded by the source corpus.

The Nrf2–Keap1 signaling pathway is key to cell defense and survival pathways. Nrf2 can protect cells and tissues from toxicants and carcinogens, and several Nrf2 activators are currently being tested as chemopreventive compounds. However, several studies also suggest that Nrf2 may protect cancer cells from chemotherapeutic agents and promote cancer cell proliferation. Here, Jaramillo and Zhang provide an overview of the Nrf2–Keap1 signaling pathway in cancer. They discuss the dual role of Nrf2 in cancer and the challenges in developing Nrf2-based drugs for chemoprevention and therapy.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/3a255a302f8ec03cefa3487b18ea483a969c66ec

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Citations in the corpus

An Integrated Metabolic Atlas of Clear Cell Renal Cell Carcinoma (2016, positive): “Mutations in the KEAP1/NRF2 axis have been shown to promote tumor invasiveness and resistance to oxidative stress in pancreatic cancers (DeNicola et al., 2011).”
Activation of the p62-Keap1-NRF2 Pathway Protects against Ferroptosis in Hepatocellular Carcinoma Cells (2015, background): “type and stage of the cancer.(7,8) For example, NRF2 prevents the initiation but accelerates the progression of chemical carcinogen-mediated or oncogene-mediated carcinogenesis.”
Glutathione metabolism in cancer progression and treatment resistance (2018, background): “NRF2 and KEAP1 somatic mutations have been shown to correlate with poor clinical outcome in several cancers such as renal cell carcinoma and pancreatic cancer (Jaramillo and Zhang, 2013; Kansanen et al., 2013).”
Pharmacological inhibition of cystine–glutamate exchange induces endoplasmic reticulum stress and ferroptosis (2014, background): “Mutations of both these genes are observed in numerous cancers (Jaramillo and Zhang, 2013), and we would predict that these changes enhance AKR1C expression and possibly render cells resistant to the induction of ferroptosis downstream of system xc− inhibition.”
Emerging mechanisms and disease relevance of ferroptosis (2020, background): “Nuclear factor erythroid 2-related factor 2 (NFR2) is one of the key regulators of the pathway to defend against oxidative stress [49].”
NRF2, a Transcription Factor for Stress Response and Beyond (2020, background): “NRF2, encoded by the gene nuclear factor, erythroid 2 like 2 (NFE2L2), belongs to the Cap’n’Collar (CNC) subfamily of basic leucine zipper (bZIP) transcription factors, which comprises nuclear factor erythroid-derived 2 (NFE2) and NRF1, NRF2, and NRF3 [1].”
Mitochondrial reactive oxygen species and cancer (2014, background): “increase expression of antioxidants including GPXs and glutathione synthesis and utilization genes [26,27].”
p62 links autophagy and Nrf2 signaling. (2015, background): “Conversely, constitutive activation of Nrf2, due to somatic mutations in genes regulating Nrf2, leads to tumor promotion and contributes to chemoresistance [75].”
Lifestyle, Oxidative Stress, and Antioxidants: Back and Forth in the Pathophysiology of Chronic Diseases (2020, background): “NRF2 is the primary regulator of cell survival that raises cancer progression by protecting cancer cells from ROS and DNA damage (Jaramillo and Zhang, 2013).”
Fundamentals of cancer metabolism (2016, background): “Specifically, NRF2 is activated following disruption of the interaction of NRF2 with its binding partner Kelch-like ECH-associated protein 1 (KEAP1).”
Integrative and comparative genomic analysis of HPV-positive and HPV-negative head and neck squamous cell carcinomas (2014, background): “KEAP1 binds to NFE2L2 and targets NFE2L2 for ubiquitination and subsequent degradation by the CUL3/RBX1 complex (48).”