Loss of Keap1 function activates Nrf2 and provides advantages for lung cancer cell growth.

By T. Ohta, K. Iijima, M. Miyamoto, Izumi Nakahara, Hiroshi Tanaka, Makiko Ohtsuji, Takafumi Suzuki, A. Kobayashi, J. Yokota, T. Sakiyama and 3 more. Cancer Research, 2008

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Oxidative and electrophilic stresses are sensed by Keap1, which activates Nrf2 to achieve cytoprotection by regulating the expression of drug-metabolizing and antioxidative stress enzymes/proteins. Because oxidative and electrophilic stresses cause many diseases, including cancer, we hypothesized that an abnormality in the Nrf2-Keap1 system may facilitate the growth of cancer cells. We sequenced the KEAP1 gene of 65 Japanese patients with lung cancer and identified five nonsynonymous somatic mutations at a frequency of 8%. We also identified two nonsynonymous somatic KEAP1 gene mutations and two lung cancer cell lines expressing KEAP1 at reduced levels. In lung cancer cells, low Keap1 activity (due to mutations or low-level expression) led to nuclear localization and constitutive activation of Nrf2. The latter resulted in constitutive expression of cytoprotective genes encoding multidrug resistance pumps, phase II detoxifying enzymes, and antioxidative stress enzymes/proteins. Up-regulation of these target genes in lung cancer cells led to cisplatin resistance. Nrf2 activation also stimulated growth of lung cancer-derived cell lines expressing KEAP1 at low levels and in mutant cell lines and in Keap1-null mouse embryonic fibroblasts under homeostatic conditions. Thus, inhibition of NRF2 may provide new therapeutic approaches in lung cancers with activation of Nrf2.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/06715ebb58e039de33558a43d6449621e879cea7

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Citations in the corpus

PGC1α Expression Defines a Subset of Human Melanoma Tumors with Increased Mitochondrial Capacity and Resistance to Oxidative Stress (2013, positive): “by activating mutations in Nrf2 or through inactivating mutations in KEAP1 (an Nrf2 cytoplasmic repressor) (Padmanabhan et al., 2006; Singh et al., 2006; Shibata et al., 2008; Ohta et al., 2008).”
Cisplatin Resistance: A Cellular Self-Defense Mechanism Resulting from Multiple Epigenetic and Genetic Changes (2012, background): “Ohta et al. (2008) further reported that loss of Keap1 function activated Nrf2, causing cells to become more resistant to cisplatin.”
Nrf2:INrf2(Keap1) Signaling in Oxidative Stress (2009, background): “Studies have reported mutations resulting in dysfunctional INrf2 in lung, breast, and bladder cancers [96–100].”
Molecular mechanisms of the Keap1–Nrf2 pathway in stress response and cancer evolution (2011, background): “Surprisingly, missense mutations of the KEAP1 gene have been found in human lung adenocarcinomas (Padmanabhan et al. 2006; Singh et al. 2006; Nioi & Nguyen 2007; Ohta et al. 2008; Shibata et al. 2008a; Takahashi et al. 2010).”
Oxidative Stress and Oxidative Damage in Carcinogenesis (2010, background): “In two separate studies, mutations in Keap1 were shown to provide a growth advantage for lung cancer cells (Ohta et al. 2008) and breast cancer cells (Nioi and Nguyen 2007).”
The emerging role of the Nrf2–Keap1 signaling pathway in cancer (2013, background): “Gain-of-function mutations in NRF2 and loss-of-function mutations in KEAP1 and CUL3 have been identified in several human cancers (Padmanabhan et al. 2006; Singh et al. 2006; Nioi and Nguyen 2007; Ohta et al. 2008; Shibata et al. 2008a; Li et al. 2011; Ooi et al. 2013; Sato et al. 2013).”
Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy (2008, background): “However, malignant development induced by deviated Nrf2-mediated gene expression profile appears to be more complicated because a number of genes involved in cell proliferation were found to be transcriptionally modulated by Nrf2 through glutathione as the effector (35) and the growth rate of immort”
Nrf2 is controlled by two distinct β-TrCP recognition motifs in its Neh6 domain, one of which can be modulated by GSK-3 activity. (2012, background): “This can arise as a consequence of somatic mutations or epigenetic changes that either diminish the activity of Keap1 or reduce its expression (14-20).”
Role of Glutathione in Cancer Progression and Chemoresistance (2013, background): “…of GGT-mediated prooxidant reactions could contribute to the resistance phenotype of GGT-expressing cancer cells by regulating both signal transduction pathways involved in proliferation/apoptosis balance, as well as by inducing protective adaptations in the pool of intracellular antioxidants.”
Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism (2011, background): “%) patients who had adenocarcinoma (ADC), squamous cell carcinoma (SCC), or large cell carcinoma (LCC) (21).”
The Nrf2 cell defence pathway: Keap1-dependent and -independent mechanisms of regulation. (2013, background): “cancer tissues including lung [20,21] and pancreas [22,23] and it is proposed that this provides cells with enhanced chemo-resistance as well as supporting increased proliferation thus promoting cancer growth and development [22].”
The cytoprotective role of the Keap1–Nrf2 pathway (2011, background): “For example, the knockdown of Nrf2 reduces the rate of proliferation in both the mouse liver and in cells lines, whilst the loss of Keap1 increases proliferation (Beyer et al. 2008; Ohta et al. 2008; Homma et al. 2009).”