bims-nurfca Biomed News
on NRF2 and Cancer
Issue of 2023–03–05
seven papers selected by
Caner Geyik, Istinye University
  1. Repurposed pizotifen malate targeting NRF2 exhibits anti-tumor activity through inducing ferroptosis in esophageal squamous cell carcinoma.
  2. The dark side of NRF2 in arsenic carcinogenesis.
  3. Nrf2 silencing amplifies DNA photooxidative damage to activate the STING pathway for synergistic tumor immunotherapy.
  4. NRF2 activation induces NADH-reductive stress, providing a metabolic vulnerability in lung cancer.
  5. A pan-cancer analysis shows immunoevasive characteristics in NRF2 hyperactive squamous malignancies.
  6. M2 tumor-associated macrophages resist to oxidative stress through heme oxygenase-1 in the colorectal cancer tumor microenvironment.
  7. Inhibition of Non-small Cell Lung Cancer by Ferroptosis and Apoptosis Induction through P53 and GSK-3β/Nrf2 Signal Pathways using Qingrehuoxue Formula.
  1. Oncogene. 2023 Feb 25.
    Repurposed pizotifen malate targeting NRF2 exhibits anti-tumor activity through inducing ferroptosis in esophageal squamous cell carcinoma.
    Xinyu He, Yubing Zhou, Wenjing Chen, Xiaokun Zhao, Lina Duan, Hao Zhou, Mingzhu Li, Yin Yu, Jimin Zhao, Yaping Guo, Huihui Gu, Yanan Jiang, Zigang Dong, Kangdong Liu.
      Targeted therapy attempts are needed to enhance esophageal squamous cell carcinoma (ESCC) patients' overall survival and satisfaction of life. Nuclear factor erythroid 2-related factor 2 (NRF2), as a high-confidence cancer driver gene, controls the antioxidant response, metabolic balance and redox homeostasis in cancer and is regarded as a potent molecular target for cancer treatment. Here, we attempted to find a new NRF2 inhibitor and study the underlying molecular mechanism in ESCC. We found that up-regulated NRF2 protein was negatively correlated with patient prognosis and promoted tumor proliferation in ESCC. Moreover, Pizotifen malate (PZM), a FDA-approved medication, bound to the Neh1 domain of NRF2 and prevented NRF2 protein binding to the ARE motif of target genes, suppressing transcription activity of NRF2. PZM treatment suppressed tumor development in ESCC PDX model by inducing ferroptosis via down-regulating the transcription of GPX4, GCLC, ME1 and G6PD. Our study illustrates that the over expression of NRF2 indicates poor prognosis and promotes tumor proliferation in ESCC. PZM, as a novel NRF2 inhibitor, inhibits the tumor growth by inducing ferroptosis and elucidates a potent NRF2-based therapy strategy for patients with ESCC.
    DOI:  https://doi.org/10.1038/s41388-023-02636-3
  2. Adv Pharmacol. 2023 ;pii: S1054-3589(22)00075-8. [Epub ahead of print]96 47-69
    The dark side of NRF2 in arsenic carcinogenesis.
    Matthew Dodson, Jinjing Chen, Aryatara Shakya, Annadurai Anandhan, Donna D Zhang.
      Arsenic is an environmental toxicant that significantly enhances the risk of developing disease, including several cancers. While the epidemiological evidence supporting increased cancer risk due to chronic arsenic exposure is strong, therapies tailored to treat exposed populations are lacking. This can be accredited in large part to the chronic nature and pleiotropic pathological effects associated with prolonged arsenic exposure. Despite this fact, several putative mediators of arsenic promotion of cancer have been identified. Among these, the critical transcription factor NRF2 has been shown to be a key mediator of arsenic's pro-carcinogenic effects. Importantly, the dependence of arsenic-transformed cancer cells on NRF2 upregulation exposes a targetable liability that could be utilized to treat arsenic-promoted cancers. In this chapter, we briefly introduce the "light" vs "dark" side of the NRF2 pathway. We then give a brief overview of arsenic metabolism, and discuss the epidemiological and experimental evidence that support arsenic promotion of different cancers, with a specific emphasis on mechanisms mediated by chronic, non-canonical activation of NRF2 (i.e., the "dark" side). Finally, we briefly highlight how the non-canonical NRF2 pathway plays a role in other arsenic-promoted diseases, as well as research directions that warrant further investigation.
    Keywords:  Arsenic; Cancer; Canonical vs non-canonical NRF2; Carcinogenesis; Dark side of NRF2
    DOI:  https://doi.org/10.1016/bs.apha.2022.08.002
  3. Biomaterials. 2023 Feb 27. pii: S0142-9612(23)00076-5. [Epub ahead of print]296 122068
    Nrf2 silencing amplifies DNA photooxidative damage to activate the STING pathway for synergistic tumor immunotherapy.
    Shengjie Sun, Mian Yu, Liu Yu, Wenxin Huang, Meishu Zhu, Yanan Fu, Lingchen Yan, Qiang Wang, Xiaoyuan Ji, Jing Zhao, Meiying Wu.
      Photodynamic therapy (PDT)-mediated antitumor immune response depends on oxidative stress intensity and subsequent immunogenic cell death (ICD) in tumor cells, yet the inherent antioxidant system restricts reactive oxygen species (ROS)-associated oxidative damage, which is highly correlated with the upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) and the downstream products, such as glutathione (GSH). Herein, to overcome this dilemma, we designed a versatile nanoadjuvant (RI@Z-P) to enhance the sensitivity of tumor cells to oxidative stress via Nrf2-specific small interfering RNA (siNrf2). The constructed RI@Z-P could significantly amplify photooxidative stress and achieve robust DNA oxidative damage, activating the stimulator of interferon genes (STING)-dependent immune-sensing to produce interferon-β (IFN-β). Additionally, RI@Z-P together with laser irradiation reinforced tumor immunogenicity by exposing or releasing damage-associated molecular patterns (DAMPs), showing the prominent adjuvant effect for promoting dendritic cell (DC) maturation and T-lymphocyte activation and even alleviating the immunosuppressive microenvironment to some extent.
    Keywords:  DNA oxidative damage; Immunogenic cell death; Photoimmunotherapy; STING pathway; siRNA delivery
    DOI:  https://doi.org/10.1016/j.biomaterials.2023.122068
  4. Cell Metab. 2023 Feb 22. pii: S1550-4131(23)00012-8. [Epub ahead of print]
    NRF2 activation induces NADH-reductive stress, providing a metabolic vulnerability in lung cancer.
    Tommy Weiss-Sadan, Maolin Ge, Makiko Hayashi, Magdy Gohar, Cong-Hui Yao, Adriaan de Groot, Stefan Harry, Alexander Carlin, Hannah Fischer, Lei Shi, Ting-Yu Wei, Charles H Adelmann, Konstantin Wolf, Tristan Vornbäumen, Benedikt R Dürr, Mariko Takahashi, Marianne Richter, Junbing Zhang, Tzu-Yi Yang, Vindhya Vijay, David E Fisher, Aaron N Hata, Marcia C Haigis, Raul Mostoslavsky, Nabeel Bardeesy, Thales Papagiannakopoulos, Liron Bar-Peled.
      Multiple cancers regulate oxidative stress by activating the transcription factor NRF2 through mutation of its negative regulator, KEAP1. NRF2 has been studied extensively in KEAP1-mutant cancers; however, the role of this pathway in cancers with wild-type KEAP1 remains poorly understood. To answer this question, we induced NRF2 via pharmacological inactivation of KEAP1 in a panel of 50+ non-small cell lung cancer cell lines. Unexpectedly, marked decreases in viability were observed in >13% of the cell lines-an effect that was rescued by NRF2 ablation. Genome-wide and targeted CRISPR screens revealed that NRF2 induces NADH-reductive stress, through the upregulation of the NAD+-consuming enzyme ALDH3A1. Leveraging these findings, we show that cells treated with KEAP1 inhibitors or those with endogenous KEAP1 mutations are selectively vulnerable to Complex I inhibition, which impairs NADH oxidation capacity and potentiates reductive stress. Thus, we identify reductive stress as a metabolic vulnerability in NRF2-activated lung cancers.
    Keywords:  NADH/NAD(+); NRF2-KEAP1 pathway; functional genomic; non-small cell lung cancer; oxidative phosphorylation; reductive stress
    DOI:  https://doi.org/10.1016/j.cmet.2023.01.012
  5. Redox Biol. 2023 Feb 27. pii: S2213-2317(23)00045-9. [Epub ahead of print]61 102644
    A pan-cancer analysis shows immunoevasive characteristics in NRF2 hyperactive squamous malignancies.
    Jouni Härkönen, Petri Pölönen, Ashik Jawahar Deen, Ilakya Selvarajan, Hanna-Riikka Teppo, Elitsa Y Dimova, Thomas Kietzmann, Maarit Ahtiainen, Juha P Väyrynen, Sara A Väyrynen, Hanna Elomaa, Niko Tynkkynen, Tiia Eklund, Teijo Kuopio, Eva-Maria Talvitie, Pekka Taimen, Markku Kallajoki, Minna U Kaikkonen, Merja Heinäniemi, Anna-Liisa Levonen.
      The NRF2 pathway is frequently activated in various cancer types, yet a comprehensive analysis of its effects across different malignancies is currently lacking. We developed a NRF2 activity metric and utilized it to conduct a pan-cancer analysis of oncogenic NRF2 signaling. We identified an immunoevasive phenotype where high NRF2 activity is associated with low interferon-gamma (IFNγ), HLA-I expression and T cell and macrophage infiltration in squamous malignancies of the lung, head and neck area, cervix and esophagus. Squamous NRF2 overactive tumors comprise a molecular phenotype with SOX2/TP63 amplification, TP53 mutation and CDKN2A loss. These immune cold NRF2 hyperactive diseases are associated with upregulation of immunomodulatory NAMPT, WNT5A, SPP1, SLC7A11, SLC2A1 and PD-L1. Based on our functional genomics analyses, these genes represent candidate NRF2 targets, suggesting direct modulation of the tumor immune milieu. Single-cell mRNA data shows that cancer cells of this subtype exhibit decreased expression of IFNγ responsive ligands, and increased expression of immunosuppressive ligands NAMPT, SPP1 and WNT5A that mediate signaling in intercellular crosstalk. In addition, we discovered that the negative relationship of NRF2 and immune cells are explained by stromal populations of lung squamous cell carcinoma, and this effect spans multiple squamous malignancies based on our molecular subtyping and deconvolution data.
    Keywords:  HLA-I; Interferon gamma; KEAP1; NRF2; PD-L1; Redox; SOX2; Squamous; T cells; TP63
    DOI:  https://doi.org/10.1016/j.redox.2023.102644
  6. Cancer Immunol Immunother. 2023 Mar 04.
    M2 tumor-associated macrophages resist to oxidative stress through heme oxygenase-1 in the colorectal cancer tumor microenvironment.
    Misato Ito, Kosaku Mimura, Shotaro Nakajima, Hirokazu Okayama, Katsuharu Saito, Takahiro Nakajima, Tomohiro Kikuchi, Hisashi Onozawa, Shotaro Fujita, Wataru Sakamoto, Motonobu Saito, Tomoyuki Momma, Zenichiro Saze, Koji Kono.
      M2 tumor-associated macrophages (M2-TAMs) promote cancer cell proliferation and metastasis in the TME. Our study aimed to elucidate the mechanism of increased frequency of M2-TAMs infiltration in the colorectal cancer (CRC)-TME, focusing on the resistance to oxidative stress through nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. In this study, we evaluated the correlation between M2-TAM signature and mRNA expression of antioxidant related genes using public datasets, and the expression level of antioxidants in M2-TAMs by flow cytometry and the prevalence of M2-TAMs expressing antioxidants by immunofluorescence staining using surgically resected specimens of CRC (n = 34). Moreover, we generated M0 and M2 macrophages from peripheral blood monocytes and evaluated their resistance to oxidative stress using the in vitro viability assay. Analysis of GSE33113, GSE39582, and The Cancer Genome Atlas (TCGA) datasets indicated that mRNA expression of HMOX1 (heme oxygenase-1 (HO-1)) was significantly positively correlated with M2-TAM signature (r = 0.5283, r = 0.5826, r = 0.5833, respectively). The expression level of both Nrf2 and HO-1 significantly increased in M2-TAMs compared to M1- and M1/M2-TAMs in the tumor margin, and the number of Nrf2+ or HO-1+M2-TAMs in the tumor stroma significantly increased more than those in the normal mucosa stroma. Finally, generated M2 macrophages expressing HO-1 significantly resisted to oxidative stress induced by H2O2 in comparison with generated M0 macrophages. Taken together, our results suggested that an increased frequency of M2-TAMs infiltration in the CRC-TME is related to Nrf2-HO-1 axis mediated resistance to oxidative stress.
    Keywords:  Colorectal cancer; HO-1; M2-TAM; Oxidative stress
    DOI:  https://doi.org/10.1007/s00262-023-03406-6
  7. J Cancer. 2023 ;14(3): 336-349
    Inhibition of Non-small Cell Lung Cancer by Ferroptosis and Apoptosis Induction through P53 and GSK-3β/Nrf2 Signal Pathways using Qingrehuoxue Formula.
    Fei Xu, Jingtao Zhang, Lingyun Ji, Wenqiang Cui, Jie Cui, Zhao Tang, Ning Sun, Guangming Zhang, Minghao Guo, Baojun Liu, Jingcheng Dong.
      This study aimed to elucidate the effects of Qingrehuoxue Formula (QRHXF) on NSCLC and its underlying mechanisms. Nude mouse model of subcutaneous tumors was established. QRHXF and erastin were administered orally and intraperitoneally, respectively. Mice's body weight and subcutaneous tumor volumes were measured. The effects of QRHXF on epithelial-mesenchymal transition (EMT), tumor-associated angiogenesis and matrix metalloproteinases (MMPs) were assessed. Importantly, we also analysed the anti-NSCLC of QRHXF form the aspect of ferroptosis and apoptosis and investigate its underlying mechanisms. The safety of QRHXF in mice was also evaluated. QRHXF slowed down the speed of tumor growth and visibly inhibited tumor growth. The expression levels of CD31, VEGFA, MMP2 and MMP9 were prominently suppressed by QRHXF. Furthermore, QRHXF appeared to remarkably inhibite cell proliferation and EMT by decreasing Ki67, N-cadherin and vimentin expression but elevating E-cadherin expression. There were more apoptotic cells in QRHXF group's tumor tissues, and QRHXF treatment increased BAX and cleaved-caspased 3 levels but decreased Bcl-2 levels. QRHXF significantly increased the accumulation of ROS, Fe2+, H2O2, and MDA while reduced GSH levels. SLC7A11 and GPX4 protein levels were considerably suppressed by QRHXF treatment. Moreover, QRHXF triggered ultrastructural changes in the mitochondria of tumor cells. The levels of p53 and p-GSK-3β were upregulated, whereas that of Nrf2 was downregulated in the groups treated with QRHXF. QRHXF displayed no toxicity in mice. QRHXF activated ferroptosis and apoptosis to suppress NSCLC cell progression via p53 and GSK-3β/Nrf2 signaling pathways.
    Keywords:  NSCLC; Traditional Chinese Medicine; anti-tumor; mechanism; signal pathway
    DOI:  https://doi.org/10.7150/jca.79465
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