bims-nurfca Biomed News
on NRF2 and Cancer
Issue of 2023–05–07
seven papers selected by
Caner Geyik, Istinye University
  1. A core Nrf2 gene set defined through comprehensive transcriptomic analysis predicts drug resistance and poor multi-cancer prognosis.
  2. The KEAP1-NRF2 pathway: Targets for therapy and role in cancer.
  3. Histone deacetylase inhibitor belinostat regulates metabolic reprogramming in killing KRAS-mutant human lung cancer cells.
  4. Phenolic compounds as Nrf2 inhibitors: potential applications in cancer therapy.
  5. The PRAK-NRF2 axis promotes the differentiation of Th17 cells by mediating the redox homeostasis and glycolysis.
  6. Apatinib combined with olaparib induces ferroptosis via a p53-dependent manner in ovarian cancer.
  7. Protective Effects of Piceatannol on DNA Damage in Benzo[a]pyrene-Induced Human Colon Epithelial Cells.
  1. bioRxiv. 2023 Apr 21. pii: 2023.04.20.537691. [Epub ahead of print]
    A core Nrf2 gene set defined through comprehensive transcriptomic analysis predicts drug resistance and poor multi-cancer prognosis.
    George Luo, Harshita Kumar, Kristin Aldridge, Stevie Rieger, Ethan Jiang, Ernest R Chan, Ahmed Soliman, Haider Mahdi, John J Letterio.
      The Nrf2-KEAP1 pathway plays an important role in the cellular response to oxidative stress and confers protection in diseases associated with chronic inflammation. However, chronic activation of the Nrf2 pathway may contribute to metabolic changes and disease progression in cancer. We investigated the activation of Nrf2 in human cancers and fibroblast cells through KEAP1 inhibition and cancer associated KEAP1/Nrf2 mutations. We define a core set of 14 upregulated Nrf2 target genes from seven RNA-Sequencing databases that we generated and analyzed. Additionally, we validated this universal Nrf2 target gene set through analyses of published databases. An Nrf2 activity score based on expression of these core target genes correlates with resistance to drugs such as PX-12 and necrosulfonamide but not to paclitaxel or bardoxolone methyl. We validated these findings and found Nrf2 activation also led to radioresistance in cancer cell lines. Finally, our Nrf2 score is prognostic for survival for a variety of cancers, an observation validated in additional independent cohorts. These analyses define a core Nrf2 gene set that is robust, versatile, and useful for predicting drug resistance and cancer prognosis.
    SIGNIFICANCE: The frequent activation of Nrf2 observed in cancer cells confers protection from oxidative stress, cytotoxic chemotherapeutic agents and radiation. We define a 'Nrf2 gene signature' that is comprised of 14 target genes and faithfully predicts increased Nrf2 activity, selective drug and radiation resistance in cancer cell lines, and a worse clinical prognosis in a variety of human cancers.
    DOI:  https://doi.org/10.1101/2023.04.20.537691
  2. Redox Biol. 2023 Apr 29. pii: S2213-2317(23)00127-1. [Epub ahead of print]63 102726
    The KEAP1-NRF2 pathway: Targets for therapy and role in cancer.
    Simone Adinolfi, Tommi Patinen, Ashik Jawahar Deen, Sini Pitkänen, Jouni Härkönen, Emilia Kansanen, Jenni Küblbeck, Anna-Liisa Levonen.
      The KEAP1-NRF2 pathway is the key regulator of cellular defense against both extrinsic and intrinsic oxidative and electrophilic stimuli. Since its discovery in the 1990s, its seminal role in various disease pathologies has become well appreciated, motivating research to elucidate the intricacies of NRF2 signaling and its downstream effects to identify novel targets for therapy. In this graphical review, we present an updated overview of the KEAP1-NRF2 signaling, focusing on the progress made within the past ten years. Specifically, we highlight the advances made in understanding the mechanism of activation of NRF2, resulting in novel discoveries in its therapeutic targeting. Furthermore, we will summarize new findings in the rapidly expanding field of NRF2 in cancer, with important implications for its diagnostics and treatment.
    Keywords:  Cancer; Gene regulation; KEAP1; NRF2
    DOI:  https://doi.org/10.1016/j.redox.2023.102726
  3. Mol Carcinog. 2023 May 05.
    Histone deacetylase inhibitor belinostat regulates metabolic reprogramming in killing KRAS-mutant human lung cancer cells.
    Rebecca M Peter, Md Shahid Sarwar, Sarah Z Mostafa, Yujue Wang, Xiaoyang Su, Ah-Ng Kong.
      Kirsten rat sarcoma virus (KRAS) oncogene, found in 20%-25% of lung cancer patients, potentially regulates metabolic reprogramming and redox status during tumorigenesis. Histone deacetylase (HDAC) inhibitors have been investigated for treating KRAS-mutant lung cancer. In the current study, we investigate the effect of HDAC inhibitor (HDACi) belinostat at clinically relevant concentration on nuclear factor erythroid 2-related factor 2 (NRF2) and mitochondrial metabolism for the treatment of KRAS-mutant human lung cancer. LC-MS metabolomic study of belinostat on mitochondrial metabolism was performed in G12C KRAS-mutant H358 non-small cell lung cancer cells. Furthermore, l-methionine (methyl-13 C) isotope tracer was used to explore the effect of belinostat on one-carbon metabolism. Bioinformatic analyses of metabolomic data were performed to identify the pattern of significantly regulated metabolites. To study the effect of belinostat on redox signaling ARE-NRF2 pathway, luciferase reporter activity assay was done in stably transfected HepG2-C8 cells (containing pARE-TI-luciferase construct), followed by qPCR analysis of NRF2 and its target gene in H358 cells, which was further confirmed in G12S KRAS-mutant A549 cells. Metabolomic study reveals significantly altered metabolites related to redox homeostasis, including tricarboxylic acid (TCA) cycle metabolites (citrate, aconitate, fumarate, malate, and α-ketoglutarate); urea cycle metabolites (Arginine, ornithine, argino-succinate, aspartate, and fumarate); and antioxidative glutathione metabolism pathway (GSH/GSSG and NAD/NADH ratio) after belinostat treatment. 13 C stable isotope labeling data indicates potential role of belinostat in creatine biosynthesis via methylation of guanidinoacetate. Moreover, belinostat downregulated the expression of NRF2 and its target gene NAD(P)H:quinone oxidoreductase 1 (NQO1), indicating anticancer effect of belinostat is mediated, potentially via Nrf2-regulated glutathione pathway. Another HDACi panobinostat also showed potential anticancer effect in both H358 and A549 cells via Nrf2 pathway. In summary, belinostat is effective in killing KRAS-mutant human lung cancer cells by regulating mitochondrial metabolism which could be used as biomarkers for preclinical and clinical studies.
    Keywords:  HDAC inhibitor; KRAS mutation; NRF2; lung cancer; mitochondrial metabolism
    DOI:  https://doi.org/10.1002/mc.23551
  4. Cell Commun Signal. 2023 May 01. 21(1): 89
    Phenolic compounds as Nrf2 inhibitors: potential applications in cancer therapy.
    Javad Sharifi-Rad, Veronique Seidel, Michalak Izabela, Margalida Monserrat-Mequida, Antoni Sureda, Valeska Ormazabal, Felipe A Zuniga, Shivaprasad Shetty Mangalpady, Raffaele Pezzani, Alibek Ydyrys, Gulmira Tussupbekova, Miquel Martorell, Daniela Calina, William C Cho.
      Cancer is a leading cause of death worldwide and involves an oxidative stress mechanism. The transcription factor Nrf2 has a crucial role in cytoprotective response against oxidative stress, including cancer growth and progression and therapy resistance. For this reason, inhibitors of Nrf2 are new targets to be studied. Traditional plant-based remedies rich in phytochemicals have been used against human cancers and phenolic compounds are known for their chemopreventive properties. This comprehensive review offers an updated review of the role of phenolic compounds as anticancer agents due to their action on Nrf2 inhibition. In addition, the role of naturally-occurring bioactive anticancer agents are covered in the clinical applications of polyphenols as Nrf2 inhibitors. Video Abstract.
    Keywords:  Apoptosis; Cancer; Cytotoxicity; Nrf2; Oxidative stress; Phenolic compounds
    DOI:  https://doi.org/10.1186/s12964-023-01109-0
  5. Proc Natl Acad Sci U S A. 2023 May 09. 120(19): e2212613120
    The PRAK-NRF2 axis promotes the differentiation of Th17 cells by mediating the redox homeostasis and glycolysis.
    Ziheng Zhao, Yan Wang, Yuhan Gao, Yurong Ju, Ye Zhao, Zhaofei Wu, Shuaixin Gao, Boyang Zhang, Xuewen Pang, Yu Zhang, Wei Wang.
      Oxidative stress is a key feature in both chronic inflammation and cancer. P38 regulated/activated protein kinase (PRAK) deficiency can cause functional disorders in neutrophils and macrophages under high oxidative stress, but the precise mechanisms by which PRAK regulates reactive oxygen species (ROS) elimination and its potential impact on CD4+ T helper subset function are unclear. The present study reveals that the PRAK-NF-E2-related factor 2(NRF2) axis is essential for maintaining the intracellular redox homeostasis of T helper 17(Th17) cells, thereby promoting Th17 cell differentiation and antitumor effects. Through mechanistic analysis, we identify NRF2 as a novel protein substrate of PRAK and find that PRAK enhances the stability of the NRF2 protein through phosphorylation NRF2 Serine(S) 558 independent of protein ubiquitination. High accumulation of cellular ROS caused by loss of PRAK disrupts both glycolysis and PKM2-dependent phosphorylation of STAT3, which subsequently impairs the differentiation of Th17 cells. As a result, Prak knockout (KO) mice display significant resistance to experimental autoimmune encephalomyelitis (EAE) but impaired antitumor immunity in a MC38 tumor model. This work reveals that the PRAK-NRF2-mediated antioxidant pathway is a metabolic checkpoint that controls Th17-cell glycolysis and differentiation. Targeting PRAK is a promising strategy for maintaining an active ROS scavenging system and may lead to potent Th17 cell antitumor immunity.
    Keywords:  NRF2; PRAK; ROS; Th17; glycolysis
    DOI:  https://doi.org/10.1073/pnas.2212613120
  6. J Cancer Res Clin Oncol. 2023 Apr 29.
    Apatinib combined with olaparib induces ferroptosis via a p53-dependent manner in ovarian cancer.
    Wang Yue, Gu Yupeng, Cao Jun, Jiang Kui.
       OBJECTIVE: PARP inhibitors combined with antiangiogenic drugs have been reported to improve outcomes in BRCA wild-type ovarian cancer patients, the mechanism of the combination is unclear. In this study, we explored the mechanism of apatinib combined with olaparib in the treatment of ovarian cancer.
    METHODS: In this study, human ovarian cancer cell lines A2780 and OVCAR3 were used as experimental objects, and the expression of ferroptosis-related protein GPX4 after treatment with apatinib and olaparib was detected by Western blot. The SuperPred database was used to predict the target of the combined action of apatinib and olaparib, and the predicted results were verified by Western blot experiment to explore the mechanism of ferroptosis induced by apatinib and olaparib.
    RESULTS: Apatinib combined with olaparib-induced ferroptosis in p53 wild-type cells, and p53 mutant cells developed drug resistance. The p53 activator RITA sensitized drug-resistant cells to ferroptosis induced by apatinib combined with olaparib. Apatinib combined with olaparib-induced ferroptosis via a p53-dependent manner in ovarian cancer. Further studies showed that apatinib combined with olaparib-induced ferroptosis by inhibiting the expression of Nrf2 and autophagy, thereby inhibiting the expression of GPX4. The Nrf2 activator RTA408 and the autophagy activator rapamycin rescued the combination drug-induced ferroptosis.
    CONCLUSION: This discovery revealed the specific mechanism of ferroptosis induced by apatinib combined with olaparib in p53 wild-type ovarian cancer cells and provided a theoretical basis for the clinical combined use of apatinib and olaparib in p53 wild-type ovarian cancer patients.
    Keywords:  Apatinib; Ferroptosis; Nrf2; Olaparib; p53
    DOI:  https://doi.org/10.1007/s00432-023-04811-1
  7. J Agric Food Chem. 2023 May 04.
    Protective Effects of Piceatannol on DNA Damage in Benzo[a]pyrene-Induced Human Colon Epithelial Cells.
    Chun-Han Chang, You-Tsz Lien, Wei-Sheng Lin, Kalyanam Nagabhushanam, Chi-Tang Ho, Min-Hsiung Pan.
      Evidence shows that the dietary intake of polycyclic aromatic hydrocarbons (PAHs) from food processing induces the cellular DNA damage response and leads to the development of colorectal cancer (CRC). Therefore, protecting from cellular DNA damage might be an effective strategy in preventing CRC. Benzo[a]pyrene (B[a]P) was used as a CRC initiator in the present study. Compared with other stilbenoids, piceatannol (PIC) showed the most effective inhibition of B[a]P-induced cytochrome P450 1B1 (CYP1B1) protein expression in NCM460 normal human colon epithelial cells. PIC treatment alleviated DNA migration and enhanced the expression of DNA-repair-related proteins, including histone 2AX (H2AX), checkpoint kinase 1 (Chk1), and p53, in B[a]P-induced NCM460 cells. The 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay, flow cytometry, and enzyme-linked immunosorbent assay (ELISA) revealed that PIC exerted antioxidative effects on NCM460 cells by increasing the glutathione (GSH) content and scavenging the excess intracellular reactive oxygen species (ROS) induced by B[a]P. Furthermore, PIC suppressed B[a]P-induced CYP1B1 protein expression and stimulated miR-27b-3p expression. The upregulation of phase II detoxification enzymes, such as nicotinamide adenine dinucleotide phosphate (NADPH) and quinone oxidoreductase 1 (NQO1), and the antioxidative enzyme, heme oxygenase 1 (HO-1), via the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway was observed in the PIC-treated group. Our results suggest that PIC is a potential CRC-blocking agent due to its ability to alleviate DNA damage, decrease intracellular ROS production, modulate the metabolism and detoxification of B[a]P, and activate the Nrf2 signaling pathway in B[a]P-induced NCM460 cells.
    Keywords:  CYP1B1; NCM460; Nrf2; benzo[a]pyrene; colorectal cancer; piceatannol
    DOI:  https://doi.org/10.1021/acs.jafc.3c00874
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