bims-nurfca Biomed News
on NRF2 and Cancer
Issue of 2023–10–29
eleven papers selected by
Caner Geyik, Istinye University
  1. "Keaping" an Eye on the NRF2 Signature Score: Expanding Its Applicability in Lung Cancer.
  2. Targeting the NF-E2-related factor 2 pathway for overcoming leukemia.
  3. Synergistic Effects of Tranylcypromine and NRF2 inhibitor: A Repurposing Strategy for Effective Cancer Therapy.
  4. NRF2 connects Src tyrosine kinase to ferroptosis resistance in glioblastoma.
  5. FOXA2 Suppression by TRIM36 Exerts Anti-Tumor Role in Colorectal Cancer Via Inducing NRF2/GPX4-Regulated Ferroptosis.
  6. KEAP1 mutation in lung adenocarcinoma promotes immune evasion and immunotherapy resistance.
  7. KEAP1/NRF2 Mutations in Stem Cells Define an Aggressive Subset of Head and Neck Cancer Patients Who Have a Poor Prognosis, Lung Metastasis, and Therapeutic Failure.
  8. STC2 is a potential biomarker of hepatocellular carcinoma with its expression being upregulated in Nrf1α-deficient cells, but downregulated in Nrf2-deficient cells.
  9. Monocarboxylate Transporter-1 (MCT1)-Mediated Lactate Uptake Protects Pancreatic Adenocarcinoma Cells from Oxidative Stress during Glutamine Scarcity Thereby Promoting Resistance against Inhibitors of Glutamine Metabolism.
  10. A Transcriptomic Approach Outperforms Mutational Analysis to Identify KEAP1/NFE2L2 Pathway Activation in Patients With NSCLC.
  11. Biomarkers in Laryngeal Squamous Cell Carcinoma: The Literature Review.
  1. J Thorac Oncol. 2023 11;pii: S1556-0864(23)00721-9. [Epub ahead of print]18(11): e126-e128
    "Keaping" an Eye on the NRF2 Signature Score: Expanding Its Applicability in Lung Cancer.
    Yongliang Niu, Feng Yao, Haitang Yang.
      
    DOI:  https://doi.org/10.1016/j.jtho.2023.08.001
  2. Int J Biol Macromol. 2023 Oct 25. pii: S0141-8130(23)04492-6. [Epub ahead of print] 127594
    Targeting the NF-E2-related factor 2 pathway for overcoming leukemia.
    Mohammad Sadra Harifi-Mood, Mahtab Daroudi, Majid Darroudi, Kobra Naseri, Saeed Samarghandian, Tahereh Farkhondeh.
      Leukemia is cancer of the body's blood-forming tissues, including the bone marrow and the lymphatic system. There are many types of leukemia that some of them occur in children and the others are more common in adults. Currently, there are many different chemotherapy agents for leukemia while chemoresistance increases the survival of the leukemic cells. One of the main reasons of chemoresistance, is a transcription factor called Nuclear factor erythroid 2-Related Factor 2 (NRF2). An increase in NRF2 expression in leukemic cells which are being treated with chemotherapy agents, can increase the survival of these cells in the presence of therapeutics. Accordingly, the inhibition of NRF2 by different methods as a cotreatment with classical chemotherapy agents, can be a promising procedure in leukemia treatment. In this study we focus on the association of NRF2 and leukemia and targeting it as a new therapeutic method in leukemia treatment.
    Keywords:  AML; Blood cancer; Chemoresistance; Chemotherapy; Leukemia; NRF2; Oxidative stress; Pediatrics leukemia; ROS
    DOI:  https://doi.org/10.1016/j.ijbiomac.2023.127594
  3. ChemMedChem. 2023 Oct 23. e202300282
    Synergistic Effects of Tranylcypromine and NRF2 inhibitor: A Repurposing Strategy for Effective Cancer Therapy.
    Delos Chen, Skye Chen, Fangheng Zhou, Lan Bo Chen, Ming-Wei Chen.
      Drug repurposing has emerged as an attractive strategy for accelerating drug discovery for cancer treatment. In this study, we investigated combining Tranylcypromine (TCP) with a number of well-characterized drugs. Among these combinations, ML385 exhibited synergistic effects in combination with TCP. Specifically, our results showed that the combination of TCP and ML385 resulted in a significant reduction in tumor proliferation while neither drug affected cancer cell growth meaningfully on its own. While further studies are needed to understand fully the extent of the synergistic efficacy, the underlying respective mechanisms and the potential side effects of this approach, our study has yielded a promising start for the development of an effective combination cancer therapy.
    Keywords:  combination cancer therapy, drug repurposing, Nrf2, LSD1, gene knockout
    DOI:  https://doi.org/10.1002/cmdc.202300282
  4. Life Sci Alliance. 2024 01;pii: e202302205. [Epub ahead of print]7(1):
    NRF2 connects Src tyrosine kinase to ferroptosis resistance in glioblastoma.
    Claudia Cirotti, Irene Taddei, Claudia Contadini, Claudia Di Girolamo, Gerardo Pepe, Marco De Bardi, Giovanna Borsellino, Manuela Helmer-Citterich, Daniela Barilà.
      Glioblastoma is a severe brain tumor characterized by an extremely poor survival rate of patients. Glioblastoma cancer cells escape to standard therapeutic protocols consisting of a combination of ionizing radiation and temozolomide alkylating drugs that trigger DNA damage by rewiring of signaling pathways. In recent years, the up-regulation of factors that counteract ferroptosis has been highlighted as a major driver of cancer resistance to ionizing radiation, although the molecular connection between the activation of oncogenic signaling and the modulation of ferroptosis has not been clarified yet. Here, we provide the first evidence for a molecular connection between the constitutive activation of tyrosine kinases and resistance to ferroptosis. Src tyrosine kinase, a central hub on which deregulated receptor tyrosine kinase signaling converge in cancer, leads to the stabilization and activation of NRF2 pathway, thus promoting resistance to ionizing radiation-induced ferroptosis. These data suggest that the up-regulation of the Src-NRF2 axis may represent a vulnerability for combined strategies that, by targeting ferroptosis resistance, enhance radiation sensitivity in glioblastoma.
    DOI:  https://doi.org/10.26508/lsa.202302205
  5. Adv Sci (Weinh). 2023 Oct 24. e2304521
    FOXA2 Suppression by TRIM36 Exerts Anti-Tumor Role in Colorectal Cancer Via Inducing NRF2/GPX4-Regulated Ferroptosis.
    Xin Liu, Chunli Yan, Chunxiao Chang, Fansong Meng, Wenjie Shen, Song Wang, Yi Zhang.
      The forkhead box transcription factor A2 (FOXA2) is a transcription factor and plays a key role in embryonic development, metabolism homeostasis and tumor cell proliferation; however, its regulatory potential in CRC is not fully understood. Here, it is found that FOXA2 expression is markedly up-regulated in tumor samples of CRC patients as compared with the normal tissues, which is closely associated with the worse survival in patients with CRC. Notably, a positive correlation between FOXA2 and nuclear factor erythroid 2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPX4) gene expression is observed in CRC patients. Mechanistically, FOXA2 depletion weakens the activation of Nrf2 pathway and decreases GPX4 level in CRC cells, thereby leading to ferroptosis, which is further supported by bioinformatic analysis. More intriguingly, the E3 ubiquitin ligase tripartite motif containing 36 (TRIM36) is identified as a key suppressor of FOXA2, and it is observed that TRIM36 can directly interact with FOXA2 and induce its K48-linked polyubiquitination, resulting in FOXA2 protein degradation in vitro. Taken together, all the studies demonstrate that FOXA2 mediated by TRIM36 promotes CRC progression by inhibiting the Nrf2/GPX4 ferroptosis signaling pathway, thus providing a new therapeutic target for CRC treatment.
    Keywords:  FOXA2; Nrf2/GPX4; TRIM36; colorectal cancer (CRC); ferroptosis
    DOI:  https://doi.org/10.1002/advs.202304521
  6. Cell Rep. 2023 Oct 25. pii: S2211-1247(23)01307-4. [Epub ahead of print]42(11): 113295
    KEAP1 mutation in lung adenocarcinoma promotes immune evasion and immunotherapy resistance.
    Anastasia-Maria Zavitsanou, Ray Pillai, Yuan Hao, Warren L Wu, Eric Bartnicki, Triantafyllia Karakousi, Sahith Rajalingam, Alberto Herrera, Angeliki Karatza, Ali Rashidfarrokhi, Sabrina Solis, Metamia Ciampricotti, Anna H Yeaton, Ellie Ivanova, Corrin A Wohlhieter, Terkild B Buus, Makiko Hayashi, Burcu Karadal-Ferrena, Harvey I Pass, John T Poirier, Charles M Rudin, Kwok-Kin Wong, Andre L Moreira, Kamal M Khanna, Aristotelis Tsirigos, Thales Papagiannakopoulos, Sergei B Koralov.
      Lung cancer treatment has benefited greatly through advancements in immunotherapies. However, immunotherapy often fails in patients with specific mutations like KEAP1, which are frequently found in lung adenocarcinoma. We established an antigenic lung cancer model and used it to explore how Keap1 mutations remodel the tumor immune microenvironment. Using single-cell technology and depletion studies, we demonstrate that Keap1-mutant tumors diminish dendritic cell and T cell responses driving immunotherapy resistance. This observation was corroborated in patient samples. CRISPR-Cas9-mediated gene targeting revealed that hyperactivation of the NRF2 antioxidant pathway is responsible for diminished immune responses in Keap1-mutant tumors. Importantly, we demonstrate that combining glutaminase inhibition with immune checkpoint blockade can reverse immunosuppression, making Keap1-mutant tumors susceptible to immunotherapy. Our study provides new insight into the role of KEAP1 mutations in immune evasion, paving the way for novel immune-based therapeutic strategies for KEAP1-mutant cancers.
    Keywords:  CD103 DC; CP: Cancer; CP: Immunology; KEAP1; LUAD; NRF2; NSCLC; T cell; adenocarcinoma; immune surveillance; immunotherapy; lung cancer
    DOI:  https://doi.org/10.1016/j.celrep.2023.113295
  7. Cancers (Basel). 2023 Oct 16. pii: 5006. [Epub ahead of print]15(20):
    KEAP1/NRF2 Mutations in Stem Cells Define an Aggressive Subset of Head and Neck Cancer Patients Who Have a Poor Prognosis, Lung Metastasis, and Therapeutic Failure.
    Syed S Islam, Bedri Karakas, Abdelilah Aboussekhra, Abu Shadat M Noman.
      Mutations in Keap1/Nrf2 in head and neck cancer result in abnormal cell growth. Progenitor cells, bulk tumor cells, and head and neck cancer stem cells (HN-CSCs) may all harbor these mutations. Nevertheless, whether Keap1/Nrf2 mutations in HN-CSCs have an impact on clinical outcomes is unknown. Cancerous HN-CSCs and benign stem cells were obtained from freshly resected head and neck cancer patients (n = 50) via flow cytometry cell sorting and tested for Keap1/Nrf2 mutations. The existence of Keap1/Nrf2 mutations in HN-CSCs, as well as their correlations with tumor mutations, pathologic tumor stage, tumor histologic grades, lung metastasis, treatment outcomes, and the patient's age and conditions, are assessed at the last follow-up visit. Thirteen tumors were found to have Keap1/Nrf2 mutations in their HN-CSCs. More than half of the lung metastases and disease progression occurred in HN-CSCs with mutations. Patients whose tumors carried Keap1/Nrf2 mutations in their HN-CSCs had significantly shorter progression-free survival, overall survival, and time of treatment failure than their non-HN-CSC counterparts. These associations were partly driven by HN-CSCs, in which Keap1/Nrf2 mutations were overrepresented in fast progressors and associated with an increased risk of disease progression. Our findings suggest that molecular genotyping of HN-CSCs may facilitate personalized treatment strategies and assist in identifying patients who are likely to benefit from chemotherapy.
    Keywords:  HN-CSCs; Keap1; Nrf2; fast progressors; head and neck cancer
    DOI:  https://doi.org/10.3390/cancers15205006
  8. Int J Biol Macromol. 2023 Oct 20. pii: S0141-8130(23)04472-0. [Epub ahead of print] 127575
    STC2 is a potential biomarker of hepatocellular carcinoma with its expression being upregulated in Nrf1α-deficient cells, but downregulated in Nrf2-deficient cells.
    Qiqi Bu, Yangxu Deng, Qing Wang, Rongzhen Deng, Shaofan Hu, Zhigang Pei, Yiguo Zhang.
      Nrf1 (encoded by Nfe2l1) and Nrf2 (encoded by Nfe2l2), as two key members of the CNC-bZIP transcription factor, exhibit significant functional differences in their pathophysiology. Our previous findings demonstrated that loss of Nrf1α (i.e., a full-length isoform of Nrf1) promotes HepG2-derived tumor growth in xenograft mice, but malgrowth of the xenograft tumor is significantly suppressed by knockout of Nrf2. To gain insights into the mechanism underlying such marked distinctions in their pathologic phenotypes, we mined transcriptome data from liver cancer in the TCGA database to establish a prognostic model and calculate predicted risk scores for each cell line. The results revealed that knockout of Nrf1α markedly increased the risk score in HepG2 cells, whereas the risk score was reduced by knockout of Nrf2. Notably, stanniocalcin 2 (STC2), a biomarker associated with liver cancer, that is upexpressed in hepatocellular carcinoma (HCC) tissues with a reduction in the overall survival ratio of those patients. We observed increased expression levels of STC2 in Nrf1α-/- cells but decreased expression in Nrf2-/- cells. These findings suggested that STC2 may play a role in mediating the distinction between Nrf1α-/- and Nrf2-/-. Such potential function of STC2 was further corroborated through a series of experiments combined with transcriptomic sequencing. The results revealed that STC2 functions as a dominant tumor-promoter, because the STC2-leading increases in clonogenicity of hepatoma cells and malgrowth of relevant xenograft tumor were almost completely abolished in STC2-/- cells. Together, these demonstrate that STC2 could be paved as a potential therapeutic target, albeit as a diagnostic marker, for HCC.
    Keywords:  Hepatocellular carcinoma; Nrf1α; Nrf2; Prognostic model; STC2
    DOI:  https://doi.org/10.1016/j.ijbiomac.2023.127575
  9. Antioxidants (Basel). 2023 Sep 30. pii: 1818. [Epub ahead of print]12(10):
    Monocarboxylate Transporter-1 (MCT1)-Mediated Lactate Uptake Protects Pancreatic Adenocarcinoma Cells from Oxidative Stress during Glutamine Scarcity Thereby Promoting Resistance against Inhibitors of Glutamine Metabolism.
    Nourhane Ammar, Maya Hildebrandt, Claudia Geismann, Christian Röder, Timo Gemoll, Susanne Sebens, Ania Trauzold, Heiner Schäfer.
      Metabolic compartmentalization of stroma-rich tumors, like pancreatic ductal adenocarcinoma (PDAC), greatly contributes to malignancy. This involves cancer cells importing lactate from the microenvironment (reverse Warburg cells) through monocarboxylate transporter-1 (MCT1) along with substantial phenotype alterations. Here, we report that the reverse Warburg phenotype of PDAC cells compensated for the shortage of glutamine as an essential metabolite for redox homeostasis. Thus, oxidative stress caused by glutamine depletion led to an Nrf2-dependent induction of MCT1 expression in pancreatic T3M4 and A818-6 cells. Moreover, greater MCT1 expression was detected in glutamine-scarce regions within tumor tissues from PDAC patients. MCT1-driven lactate uptake supported the neutralization of reactive oxygen species excessively produced under glutamine shortage and the resulting drop in glutathione levels that were restored by the imported lactate. Consequently, PDAC cells showed greater survival and growth under glutamine depletion when utilizing lactate through MCT1. Likewise, the glutamine uptake inhibitor V9302 and glutaminase-1 inhibitor CB839 induced oxidative stress in PDAC cells, along with cell death and cell cycle arrest that were again compensated by MCT1 upregulation and forced lactate uptake. Our findings show a novel mechanism by which PDAC cells adapt their metabolism to glutamine scarcity and by which they develop resistance against anticancer treatments based on glutamine uptake/metabolism inhibition.
    Keywords:  anaplerosis; drug resistance; pancreas; tumor metabolism
    DOI:  https://doi.org/10.3390/antiox12101818
  10. J Thorac Oncol. 2023 11;pii: S1556-0864(23)00722-0. [Epub ahead of print]18(11): 1431-1433
    A Transcriptomic Approach Outperforms Mutational Analysis to Identify KEAP1/NFE2L2 Pathway Activation in Patients With NSCLC.
    Sara Hijazo-Pechero, Cristina Muñoz-Pinedo, Ernest Nadal.
      
    DOI:  https://doi.org/10.1016/j.jtho.2023.08.002
  11. Cancers (Basel). 2023 Oct 22. pii: 5096. [Epub ahead of print]15(20):
    Biomarkers in Laryngeal Squamous Cell Carcinoma: The Literature Review.
    Barbara Verro, Carmelo Saraniti, Daniela Carlisi, Carlos Chiesa-Estomba, Antonino Maniaci, Jerome R Lechien, Miguel Mayo, Nicolas Fakhry, Marianna Lauricella.
      Laryngeal squamous cell carcinoma (LSCC) is the second most common cancer among head and neck cancers. Despite a lower incidence of laryngeal carcinoma, new diagnostic techniques, and more targeted therapies, the overall survival has not changed significantly in the last decades, leading to a negative prognosis in advanced stages. Recently, several studies have focused on the identification of biomarkers that may play a critical role in the pathogenesis of LSCC. Reviewing the literature on the main databases, this study aims to investigate the role of some biomarkers in LSCC that are correlated with oxidative stress and inflammation: heat shock proteins; metallothioneins; nuclear factor erythroid 2-related factor 2; heme oxygenase; cyclooxygenase-2; and micro ribonucleic acids. This review shows that biomarker expression depends on the type, grade of differentiation, stage, and site of carcinoma. In addition, the role of these biomarkers in LSCC is still little-known and little-studied. However, the study of biomarker expression and the detection of a possible correlation with patients' epidemiological, clinicopathological, and therapeutics data may lead to better awareness and knowledge of the tumor, to the identification of the best therapeutic strategy, and the most proper follow-up protocol tailored for each patient. In conclusion, the achievement of these goals may improve the prognosis of LSCC patients.
    Keywords:  biomarkers; cyclooxygenase-2; heat shock proteins; heme oxygenase; laryngeal cancer; larynx; metallothioneins; micro ribonucleic acid; nuclear factor erythroid 2-related factor 2
    DOI:  https://doi.org/10.3390/cancers15205096
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