bims-nurfca Biomed News
on NRF2 and Cancer
Issue of 2024–08–11
seven papers selected by
Caner Geyik, Istinye University
  1. Nrf2/ASPM axis regulated vasculogenic mimicry formation in hepatocellular carcinoma under hypoxia.
  2. Cytochrome P450 F3 promotes colorectal cancer via inhibiting NRF2-mediated ferroptosis.
  3. Exosomal circ-0100519 promotes breast cancer progression via inducing M2 macrophage polarisation by USP7/NRF2 axis.
  4. Lung-MAP Next Generation Sequencing Analysis of Advanced Squamous Cell Lung Cancers (SWOG S1400).
  5. Nrf2 as a regulator of energy metabolism and mitochondrial function.
  6. Epigenetic repression of de novo cysteine synthetases induces intra-cellular accumulation of cysteine in hepatocarcinoma by up-regulating the cystine uptake transporter xCT.
  7. Human NQO1 as a Selective Target for Anticancer Therapeutics and Tumor Imaging.
  1. J Gastroenterol. 2024 Aug 03.
    Nrf2/ASPM axis regulated vasculogenic mimicry formation in hepatocellular carcinoma under hypoxia.
    Yueyao Zhang, Na Che, Song Wang, Jie Meng, Nan Zhao, Jiyuan Han, Xueyi Dong, Yanlei Li, Jing Mo, Xiulan Zhao, Tieju Liu.
       BACKGROUND: Hypoxic microenvironment is a common feature of most solid tumors including hepatocellular carcinoma (HCC). Vasculogenic mimicry (VM) formation by tumor cells could provide blood supply to tumor cells under hypoxia. NFE2 like basic leucine zipper (bZIP) transcription factor 2 (Nrf2), a regulator of cellular homeostasis, may promote tumor progression in the hypoxic conditions. However, the role and regulatory mechanisms of Nrf2 in HCC are not fully elucidated.
    METHODS: Nrf2 and assembly factor for spindle microtubules (ASPM) expression modulations were conducted by lentiviral transfections. Western blot, immunofluorescence, ChIP-qPCR, dual-luciferase reporter gene assay, flow cytometry, RNA sequencing, multiple bioinformatics databases analysis, cell function assays in vitro, mouse model in vivo and human HCC tissues were employed to assess the effect of Nrf2/ASPM axis on HCC progression under hypoxia.
    RESULTS: Nrf2 and ASPM expression facilitated epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs) feature, and VM formation of HCC cells under hypoxia. Furthermore, Nrf2-regulated ASPM expression, via binding directly to the promoter region of ASPM and transcriptionally promoting ASPM expression. ASPM re-expression in Nrf2 knockdown cells or ASPM knockdown in Nrf2 overexpression cells reversed the cellular function caused by Nrf2. Meantime, retinol metabolism pathway was disrupted following abnormal ASPM expression. Nrf2/ASPM axis in murine models accelerated tumor growth and VM, corroborating in vitro findings. All-trans retinoic acid treatment reversed stemness and VM of HCC cells in vitro and in vivo. Clinically, Nrf2 and ASPM expressions were related to poor prognosis of HCC patients.
    CONCLUSIONS: Nrf2 drives EMT, CSCs characteristics and VM in HCC under hypoxia through the modulation of ASPM. Retinol metabolism pathway was dysregulated in HCC cells with ASPM overexpression. Nrf2/ASPM axis and related pathway provided potential therapeutic target for HCC.
    Keywords:  ASPM; Hepatocellular carcinoma; Hypoxia; Nrf2; Vasculogenic mimicry
    DOI:  https://doi.org/10.1007/s00535-024-02140-9
  2. Transl Oncol. 2024 Aug 05. pii: S1936-5233(24)00204-3. [Epub ahead of print]48 102077
    Cytochrome P450 F3 promotes colorectal cancer via inhibiting NRF2-mediated ferroptosis.
    Ziyang Xu, Cheng Xu, Jie Lu, Chenfeng He, Xinyue Wang, Dongfei Zhu, Aizhong Wang, Zhengyun Zhang, Can Jiang.
      Cytochrome P450 F3 (CYP4F3) is recognized as a disease-associated immune response initiator that is involved in the synthesis of cholesterol, steroids, and lipids. This study identified the upregulation of CYP4F3 expression in colorectal cancer (CRC) and its association with poor patient prognosis through a comparative analysis between CRC tumor tissues with normal tissues from public databases. The overexpression of CYP4F3 in CT26.wt and SW620, promoted cell proliferation and migration, a reduction of cellular oxidative stress, an up-regulation of the oxidative stress-related pathway NRF2, and an inhibition of cellular ferroptosis. Additionally, inhibition of NRF2 activity stimulated cellular ferroptosis when CYP4F3 was overexpressed. Ferroptosis, characterized by iron-dependent lipid peroxidation, is a non-apoptotic way of cell death with a critical role in cancer development. When given a ferroptosis agonist to CYP4F3-overexpression CRC cells, NRF2 was activated, and cell proliferation and migration were reduced. Furthermore, the mice subcutaneously injected with CYP4F3-overexpression CT26.wt cells formed significantly larger tumors compared to the CYP4F3-vector CT26.wt cell group. This study systematically identified an important role of CYP4F3 in CRC development as a regulator of CRC cells to escape ferroptosis via NRF2, highlighting the significance of CYP4F3 as a potential therapeutic target for CRC.
    Keywords:  CYP4F3; Colorectal cancer; Cytochrome P450; Ferroptosis; NRF2
    DOI:  https://doi.org/10.1016/j.tranon.2024.102077
  3. Clin Transl Med. 2024 Aug;14(8): e1763
    Exosomal circ-0100519 promotes breast cancer progression via inducing M2 macrophage polarisation by USP7/NRF2 axis.
    Minyu Zhuang, Xiaoqiang Zhang, Jie Ji, Hongfei Zhang, Li Shen, Yanhui Zhu, Xiaoan Liu.
       BACKGROUND: Breast cancer (BC) is one of the most prevalent malignant tumours that threatens women health worldwide. It has been reported that circular RNAs (circRNAs) play an important role in regulating tumour progression and tumour microenvironment (TME) remodelling.
    METHODS: Differentially expression characteristics and immune correlations of circRNAs in BC were verified using high-throughput sequencing and bioinformatic analysis. Exosomes were characterised by nanoparticle transmission electron microscopy and tracking analysis. The biological function of circ-0100519 in BC development was demonstrated both in vitro and in vivo. Western blotting, RNA pull-down, RNA immunoprecipitation, flow cytometry, and luciferase reporter were conducted to investigate the underlying mechanism.
    RESULTS: Circ-0100519 was significant abundant in BC tumour tissues and related to poor prognosis. It can be encapsulated into secreted exosomes, thereby promoting BC cell invasion and metastasis via inducing M2-like macrophages polarisation.Mechanistically, circ-0100519 acted as a scaffold to enhance the interaction between the deubiquitinating enzyme ubiquitin-specific protease 7 (USP7) and nuclear factor-like 2 (NRF2) in macrophages, inducing the USP7-mediated deubiquitination of NRF2. Additionally, HIF-1α could function as an upstream effector to enhance circ-0100519 transcription.
    CONCLUSIONS: Our study revealed that exosomal circ-0100519 is a potential biomarker for BC diagnosis and prognosis, and the HIF-1α inhibitor PX-478 may provide a therapeutic target for BC.
    Keywords:  HIF‐1α; NRF2; USP7; breast cancer; circ‐0100519; exosomes; macrophages
    DOI:  https://doi.org/10.1002/ctm2.1763
  4. J Thorac Oncol. 2024 Aug 05. pii: S1556-0864(24)00751-2. [Epub ahead of print]
    Lung-MAP Next Generation Sequencing Analysis of Advanced Squamous Cell Lung Cancers (SWOG S1400).
    David Kozono, Xing Hua, Michael C Wu, Khaled A Tolba, Saiama N Waqar, Konstantin H Dragnev, Haiying Cheng, Fred R Hirsch, Philip C Mack, Jhanelle E Gray, Karen Kelly, Hossein Borghaei, Roy S Herbst, David R Gandara, Mary W Redman.
       INTRODUCTION: Squamous cell cancer (SqCC) is a lung cancer subtype with few targeted therapy options. Molecular characterization, i.e., by next generation sequencing (NGS), is needed to identify potential targets. Lung-MAP SWOG S1400 enrolled patients with previously treated stage IV or recurrent SqCC to assess NGS biomarkers for therapeutic substudies.
    METHODS: Tumors underwent NGS using Foundation Medicine's FoundationOne research platform, which sequenced the exons and/or introns of 313 cancer-related genes. Mutually Exclusive Gene Set Analysis (MEGSA) and Selected Events Linked by Evolutionary Conditions across human Tumors (SELECT) were performed to identify mutually exclusive and co-occurring gene alterations. Comparisons were performed with data on 495 lung SqCC downloaded from The Cancer Genome Atlas. Cox proportional hazards models were used to examine associations between genetic variants and survival.
    RESULTS: NGS data are reported for 1672 patients enrolled on S1400 between 2014 and 2019. MEGSA identified two non-overlapping sets of mutually exclusive alterations with a false discovery rate < 15%: NFE2L2, KEAP1 and PARP4; and CDKN2A and RB1. PARP4, a relatively uncharacterized gene, showed three frequent mutations suggesting functional significance: 3116T>C (I1039T), 3176A>G (Q1059R) and 3509C>T (T1170I). NFE2L2 and KEAP1 alterations when taken together were associated with poorer survival.
    CONCLUSIONS: As the largest dataset to-date of lung SqCC profiled on a clinical trial, the S1400 NGS dataset establishes a rich resource for biomarker discovery. Mutual exclusivity of PARP4 and NFE2L2 or KEAP1 alterations suggests that PARP4 may have an uncharacterized role in a key pathway known to impact oxidative stress response and treatment resistance.
    Keywords:  PARP4; Squamous cell lung cancer; next generation sequencing
    DOI:  https://doi.org/10.1016/j.jtho.2024.07.024
  5. FEBS Lett. 2024 Aug 08.
    Nrf2 as a regulator of energy metabolism and mitochondrial function.
    Alina Luchkova, Ana Mata, Susana Cadenas.
      Nuclear factor erythroid-2-related factor 2 (Nrf2) is essential for the control of cellular redox homeostasis. When activated, Nrf2 elicits cytoprotective effects through the expression of several genes encoding antioxidant and detoxifying enzymes. Nrf2 can also improve antioxidant defense via the pentose phosphate pathway by increasing NADPH availability to regenerate glutathione. Microarray and genome-wide localization analyses have identified many Nrf2 target genes beyond those linked to its redox-regulatory capacity. Nrf2 regulates several intermediary metabolic pathways and is involved in cancer cell metabolic reprogramming, contributing to malignant phenotypes. Nrf2 also modulates substrate utilization for mitochondrial respiration. Here we review the experimental evidence supporting the essential role of Nrf2 in the regulation of energy metabolism and mitochondrial function.
    Keywords:  Nrf2; energy metabolism; metabolic reprogramming; mitochondria; oxidative stress; redox signaling
    DOI:  https://doi.org/10.1002/1873-3468.14993
  6. Cancer Metab. 2024 Aug 07. 12(1): 23
    Epigenetic repression of de novo cysteine synthetases induces intra-cellular accumulation of cysteine in hepatocarcinoma by up-regulating the cystine uptake transporter xCT.
    Tomoaki Yamauchi, Yumi Okano, Daishu Terada, Sai Yasukochi, Akito Tsuruta, Yuya Tsurudome, Kentaro Ushijima, Naoya Matsunaga, Satoru Koyanagi, Shigehiro Ohdo.
       BACKGROUND: The metabolic reprogramming of amino acids is critical for cancer cell growth and survival. Notably, intracellular accumulation of cysteine is often observed in various cancers, suggesting its potential role in alleviating the oxidative stress associated with rapid proliferation. The liver is the primary organ for cysteine biosynthesis, but much remains unknown about the metabolic alterations of cysteine and their mechanisms in hepatocellular carcinoma cells.
    METHODS: RNA-seq data from patients with hepatocarcinoma were analyzed using the TNMplot database. The underlying mechanism of the oncogenic alteration of cysteine metabolism was studied in mice implanted with BNL 1ME A.7 R.1 hepatocarcinoma.
    RESULTS: Database analysis of patients with hepatocellular carcinoma revealed that the expression of enzymes involved in de novo cysteine synthesis was down-regulated accompanying with increased expression of the cystine uptake transporter xCT. Similar alterations in gene expression have also been observed in a syngeneic mouse model of hepatocarcinoma. The enhanced expression of DNA methyltransferase in murine hepatocarcinoma cells caused methylation of the upstream regions of cysteine synthesis genes, thereby repressing their expression. Conversely, suppression of de novo cysteine synthesis in healthy liver cells induced xCT expression by up-regulating the oxidative-stress response factor NRF2, indicating that reduced de novo cysteine synthesis repulsively increases cystine uptake via enhanced xCT expression, leading to intracellular cysteine accumulation. Furthermore, the pharmacological inhibition of xCT activity decreased intracellular cysteine levels and suppressed hepatocarcinoma tumor growth in mice.
    CONCLUSIONS: Our findings indicate an underlying mechanism of the oncogenic alteration of cysteine metabolism in hepatocarcinoma and highlight the efficacy of alteration of cysteine metabolism as a viable therapeutic target in cancer.
    Keywords:  Cysteine metabolism; DNA methylation; Erastin; Hepatocarcinoma; NRF2; de novo cysteine synthesis; xCT
    DOI:  https://doi.org/10.1186/s40170-024-00352-4
  7. Cells. 2024 Jul 29. pii: 1272. [Epub ahead of print]13(15):
    Human NQO1 as a Selective Target for Anticancer Therapeutics and Tumor Imaging.
    A E M Adnan Khan, Viswanath Arutla, Kalkunte S Srivenugopal.
      Human NAD(P)H-quinone oxidoreductase1 (HNQO1) is a two-electron reductase antioxidant enzyme whose expression is driven by the NRF2 transcription factor highly active in the prooxidant milieu found in human malignancies. The resulting abundance of NQO1 expression (up to 200-fold) in cancers and a barely detectable expression in body tissues makes it a selective marker of neoplasms. NQO1 can catalyze the repeated futile redox cycling of certain natural and synthetic quinones to their hydroxyquinones, consuming NADPH and generating rapid bursts of cytotoxic reactive oxygen species (ROS) and H2O2. A greater level of this quinone bioactivation due to elevated NQO1 content has been recognized as a tumor-specific therapeutic strategy, which, however, has not been clinically exploited. We review here the natural and new quinones activated by NQO1, the catalytic inhibitors, and the ensuing cell death mechanisms. Further, the cancer-selective expression of NQO1 has opened excellent opportunities for distinguishing cancer cells/tissues from their normal counterparts. Given this diagnostic, prognostic, and therapeutic importance, we and others have engineered a large number of specific NQO1 turn-on small molecule probes that remain latent but release intense fluorescence groups at near-infrared and other wavelengths, following enzymatic cleavage in cancer cells and tumor masses. This sensitive visualization/quantitation and powerful imaging technology based on NQO1 expression offers promise for guided cancer surgery, and the reagents suggest a theranostic potential for NQO1-targeted chemotherapy.
    Keywords:  NQO1 turn-on probes; antioxidant enzymes; futile substrates; near-infrared fluorophores; targeted therapy; theranostic drugs; tumor imaging; tumor-selective therapies; β-lapachone
    DOI:  https://doi.org/10.3390/cells13151272
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