Somatic mutations in the KEAP1 ubiquitin ligase or its substrate NRF2 (NFE2L2) commonly occur in human cancer, resulting in constitutive NRF2-mediated transcription of cytoprotective genes. However, many tumors display high NRF2 activity in the absence of mutation, supporting alternative mechanisms of pathway activation. Previously, we and others discovered that via a competitive binding mechanism, the proteins WTX (AMER1), PALB2 and SQSTM1 bind KEAP1 to activate NRF2. Proteomic analysis of the KEAP1 protein interaction network revealed a significant enrichment of associated proteins containing an ETGE amino acid motif, which matches the KEAP1 interaction motif found in NRF2. Like WTX, PALB2, and SQSTM1, we found that the dipeptidyl peptidase 3 (DPP3) protein binds KEAP1 via an 'ETGE' motif to displace NRF2, thus inhibiting NRF2 ubiquitination and driving NRF2-dependent transcription. Comparing the spectrum of KEAP1 interacting proteins with the genomic profile of 178 squamous cell lung carcinomas characterized by The Cancer Genome Atlas revealed amplification and mRNA over-expression of the DPP3 gene in tumors that have high NRF2 activity but lacking NRF2 stabilizing mutations. We further show that tumor-derived mutations in KEAP1 are hypomorphic with respect to NRF2 inhibition and that DPP3 over-expression in the presence of these mutants further promotes NRF2 activation. Collectively, our findings support the competition model of NRF2 activation and suggest that 'ETGE'-containing proteins like DPP3 contribute to NRF2 activity in cancer.
"NRF2 stability is also regulated by the CR6-interacting factor 1 (CRIF1) under both reducing and oxidative stress conditions (Kang et al. 2010) and the glycogen synthase kinase 3b (GSK3b)/b-transducin repeat-containing protein (b-TrCP) axis (Chowdhry et al. 2013; Rada et al. 2011; Rada et al. 2012). It has been reported that stability of NRF2 is also regulated by competitive protein–protein interaction to inhibit NRF2-KEAP1 binding by various proteins such as p21 (Chen et al. 2009), the Wilms tumor gene on X chromosome (WTX) (Camp et al. 2012), p62 (Komatsu et al. 2010), the partner and localizer of BRCA2 (PALB2) (Ma et al. 2012), the dipeptidyl peptidase III (DPP3) (Hast et al. 2013), and the breast cancer susceptibility gene 1 (BRCA1) (Gorrini et al. 2013). NRF2 functions as either a protector against tumorigenesis or oncogene (DeNicola et al. 2011; Kensler and Wakabayashi 2010; Loboda et al. 2008; Muller and Hengstermann 2012). "
[Show abstract][Hide abstract] ABSTRACT: NRF2 is a nuclear transcription factor activated in response to oxidative stress and related with metabolizing of xenotoxic materials and ABC transporter mediated drug resistance. We studied the expression of mRNAs under the siRNA-mediated knockdown of NRF2 and tBHQ-treated condition in AsPC-1 metastatic pancreatic cancer cell line to understand the AsPC-1 specific role(s) of NRF2 and further to investigate the relationship between drug resistance and metastatic plasticity and mobility of AsPc1. Here we show that the genes of aldo–keto reductases, cytochrome P450 family, aldehyde dehydrogenase, thioredoxin reductase, ABC transporter and epoxide hydrolase responsible for drug metabolism or oxidative stress concisely responded to NRF2 stabilization and knockdown of NRF2. In addition the expression of PIR, a candidate of oncogene and KISS1, a suppressor of metastasis were affected by NRF2 stabilization and knockdown. Our result provide comprehensive understanding of NRF2 target genes of drug response, oxidative stress response and metastasis in AsPc-1 metastatic pancreatic cancer cell line.
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The online version of this article (doi:10.1007/s13258-014-0253-2) contains supplementary material, which is available to authorized users.
[Show abstract][Hide abstract] ABSTRACT: The Nrf2 (nuclear factor erythroid 2 [NF-E2]-related factor 2 [Nrf2])-Keap1 (Kelch-like erythroid cell-derived protein with CNC homology [ECH]-associated protein 1) signaling pathway is one of the most important cell defense and survival pathways. Nrf2 can protect cells and tissues from a variety of toxicants and carcinogens by increasing the expression of a number of cytoprotective genes. As a result, several Nrf2 activators are currently being tested as chemopreventive compounds in clinical trials. Just as Nrf2 protects normal cells, studies have shown that Nrf2 may also protect cancer cells from chemotherapeutic agents and facilitate cancer progression. Nrf2 is aberrantly accumulated in many types of cancer, and its expression is associated with a poor prognosis in patients. In addition, Nrf2 expression is induced during the course of drug resistance. Collectively, these studies suggest that Nrf2 contributes to both intrinsic and acquired chemoresistance. This discovery has opened up a broad spectrum of research geared toward a better understanding of the role of Nrf2 in cancer. This review provides an overview of (1) the Nrf2-Keap1 signaling pathway, (2) the dual role of Nrf2 in cancer, (3) the molecular basis of Nrf2 activation in cancer cells, and (4) the challenges in the development of Nrf2-based drugs for chemoprevention and chemotherapy.
Genes & development 10/2013; 27(20):2179-91. DOI:10.1101/gad.225680.113 · 10.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Nuclear factor erythroid 2-related factor 2 (Nrf2) is an essential component of cellular defence against a vast variety of endogenous and exogenous insults, including oxidative stress. Nrf2 acts as a master switch in the circuits upregulating the expression of various stress-response proteins, especially heme oxygenase-1 (HO-1). Paradoxically, however, recent studies have demonstrated oncogenic functions of Nrf2 and its major target protein HO-1. Levels of Nrf2 and HO-1 have been elevated in many different types of human malignancies, which may facilitate the remodeling of tumor microenvironment advantageous for the autonomic growth of cancer cells, metastasis, angiogenesis and tolerance to chemotherapeutic agents and radiation and photodynamic therapy. In this context, the cellular stress response or cytoprotective signaling mediated via the Nrf2-HO-1 axis is hijacked by cancer cells for their growth advantage and survival from anticancer treatment. Therefore, Nrf2 and HO-1 may represent potential therapeutic targets in the management of cancer. This review highlights the role for Nrf2 and HO-1 in proliferation of cancer cells, their tolerance/resistance to anticancer treatments, and metastasis or angiogenesis in tumor progression.
Free Radical Biology and Medicine 11/2013; 67. DOI:10.1016/j.freeradbiomed.2013.10.819 · 5.74 Impact Factor
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