bims-nurfca Biomed News
on NRF2 and Cancer
Issue of 2023‒08‒27
six papers selected by
Caner Geyik, Istinye University
  1. Nrf2--a Hidden Bridge Linking Cancer Stem Cells to Ferroptosis.
  2. TMED2 Induces Cisplatin Resistance in Breast Cancer via Targeting the KEAP1-Nrf2 Pathway.
  3. Metabolic reprogramming in Nrf2-driven proliferation of normal rat hepatocytes.
  4. Modulation of NRF2/KEAP1-Mediated Oxidative Stress for Cancer Treatment by Natural Products Using Pharmacophore-Based Screening, Molecular Docking, and Molecular Dynamics Studies.
  5. Muscle p62 stimulates the expression of antioxidant proteins alleviating cancer cachexia.
  6. A NRF2-induced secretory phenotype activates immune surveillance to remove irreparably damaged cells.
  1. Crit Rev Oncol Hematol. 2023 Aug 18. pii: S1040-8428(23)00193-2. [Epub ahead of print] 104105
    Nrf2--a Hidden Bridge Linking Cancer Stem Cells to Ferroptosis.
    Yawen Li, Halahati Tuerxun, Xingyu Liu, Yixin Zhao, Shuhui Wen, Yaping Li, Jingjing Cao, Yuguang Zhao.
      Cancer stem cells (CSCs), a small population of stem cells existing in cancer cells, are considered as the "culprits" of tumor recurrence, metastasis, and drug resistance. Ferroptosis is a promising new lead in anti-cancer therapy. Because of unique metabolic characteristics, CSCs' growth is more dependent on the iron and lipid than ordinary cancer cells. When the metabolism of iron/lipid is disordered, that is, imbalanced redox homeostasis, CSCs are more susceptible to ferroptosis. The expression of Nuclear factor E2-related factor 2 (Nrf2), a molecule playing a major regulatory role in redox homeostasis, determines whether the cells are under oxidative stress and ferroptosis occurs. Nrf2 expression level is higher in CSCs, indicating stronger dependence on Nrf2. Here we expound the unique biological and metabolic characteristics of CSCs, explore the mechanism of inducing ferroptosis by targeting Nrf2, thus providing promising new targets for eliminating aggressive tumors and achieving the goal of curing tumors.
    Keywords:  Cancer stem cells; Nrf2; ferroptosis; glutathione; oxidative stress
    DOI:  https://doi.org/10.1016/j.critrevonc.2023.104105
  2. Curr Med Sci. 2023 Aug 24.
    TMED2 Induces Cisplatin Resistance in Breast Cancer via Targeting the KEAP1-Nrf2 Pathway.
    Chen Liang, Han-Yong Zhang, Yi-Qian Wang, Ling-Ang Yang, Yu-Sen Du, Ying Luo, Tong-Cun Zhang, Yao Xu.
      OBJECTIVE: Cisplatin is the first-line treatment for breast cancer, but it faces challenges of drug resistance. This study investigated new molecular mechanisms underlying cisplatin resistance in breast cancer.METHODS: We analyzed sequencing data from the TCGA database to identify potential associations between transmembrane emp24 protein transport domain containing 2 (TMED2) and breast cancer. Western blotting, real-time PCR, CCK-8, and TUNEL assays were used to measure the effects and molecular mechanism of TMED2 on cisplatin resistance in MCF-7 and MDA-MB-231 cell lines.
    RESULTS: TMED2 was overexpressed in breast cancer and associated with poor prognosis. TMED2 increased cisplatin resistance in breast cancer cells in vitro via promoting ubiquitination of Kelch-like ECH-associated protein 1 (KEAP1), relieving inhibition of KEAP1 on nuclear factor erythroid 2-related factor 2 (Nrf2), and increasing expression of downstream drug resistance related genes, such as heme oxygenase 1 (HO-1) and NAD (P) H quinone oxidoreductase 1 (NQO1).
    CONCLUSION: We identified a new molecular mechanism by which TMED2 affects cisplatin resistance in breast cancer. Our results provide theoretical guidance for future clinical applications.
    Keywords:  KEAP1; Nrf2; TMED2; breast cancer; cisplatin resistance
    DOI:  https://doi.org/10.1007/s11596-023-2777-7
  3. Hepatology. 2023 Aug 21.
    Metabolic reprogramming in Nrf2-driven proliferation of normal rat hepatocytes.
    Marta Anna Kowalik, Keiko Taguchi, Marina Serra, Andrea Caddeo, Elisabetta Puliga, Marina Bacci, Seizo Koshiba, Jin Inoue, Eiji Hishinuma, Andrea Morandi, Silvia Giordano, Andrea Perra, Masayuki Yamamoto, Amedeo Columbano.
      BACKGROUND AIMS: Cancer cells reprogram their metabolic pathways to support bioenergetic and biosynthetic needs and to maintain their redox balance. In several human tumors the Keap1-Nrf2 system controls proliferation and metabolic reprogramming by regulating the pentose phosphate pathway (PPP). However, whether this metabolic reprogramming also occurs in normal proliferating cells is unclear.APPROACH AND RESULTS: To define the metabolic phenotype in normal proliferating hepatocytes, we induced cell proliferation in the liver by three distinct stimuli: liver regeneration by partial hepatectomy (PH) and hepatic hyperplasia induced by two direct mitogens, lead nitrate (LN) or triiodothyronine (T3). Following LN treatment, well-established features of cancer metabolic reprogramming including enhanced glycolysis, oxidative PPP, nucleic acid synthesis, NAD+/NADH synthesis and altered amino acid content as well as downregulated oxidative phosphorylation (OXPHOS) occurred in normal proliferating hepatocytes displaying Nrf2 activation. Genetic deletion of Nrf2 blunted LN-induced PPP activation and suppressed hepatocyte proliferation. Moreover, Nrf2 activation and following metabolic reprogramming did not occur when hepatocyte proliferation was induced by PH or T3.
    CONCLUSION: Many metabolic changes in cancer cells are shared by proliferating normal hepatocytes in response to a hostile environment. Nrf2 activation is essential for bridging metabolic changes with crucial components of cancer metabolic reprogramming including the activation of oxidative PPP. Our study demonstrates that matured hepatocytes exposed to LN undergo a cancer-like metabolic reprogramming and offers a rapid and useful in vivo model to study the molecular alterations underpinning the differences/similarities of metabolic changes in normal and neoplastic hepatocytes.
    DOI:  https://doi.org/10.1097/HEP.0000000000000568
  4. Molecules. 2023 Aug 10. pii: 6003. [Epub ahead of print]28(16):
    Modulation of NRF2/KEAP1-Mediated Oxidative Stress for Cancer Treatment by Natural Products Using Pharmacophore-Based Screening, Molecular Docking, and Molecular Dynamics Studies.
    Abdulrahim A Alzain, Rua M Mukhtar, Nihal Abdelmoniem, Tagyedeen H Shoaib, Wadah Osman, Marwa Alsulaimany, Ahmed K B Aljohani, Sara A Almadani, Baiaan H Alsaadi, Maryam M Althubyani, Shaimaa G A Mohamed, Gamal A Mohamed, Sabrin R M Ibrahim.
      Oxidative stress plays a significant role in the development of cancer. Inhibiting the protein-protein interaction (PPI) between Keap1 and Nrf2 offers a promising strategy to activate the Nrf2 antioxidant pathway, which is normally suppressed by the binding of Keap1 to Nrf2. This study aimed to identify natural compounds capable of targeting the kelch domain of KEAP1 using structure-based drug design methods. A pharmacophore model was constructed based on the KEAP1-inhibitor complex, leading to the selection of 6178 compounds that matched the model. Subsequently, docking and MM/GBSA analyses were conducted, resulting in the identification of 10 compounds with superior binding energies compared to the reference compound. From these, three compounds (ZINC000002123788, ZINC000002111341, and ZINC000002125904) were chosen for further investigation. Ligand-residue interaction analysis revealed specific interactions between these compounds and key residues, indicating their stability within the binding site. ADMET analysis confirmed that the selected compounds possessed desirable drug-like properties. Furthermore, molecular dynamics simulations were performed, demonstrating the stability of the ligand-protein complexes over a 100 ns duration. These findings underscore the potential of the selected natural compounds as agents targeting KEAP1 and provide valuable insights for future experimental studies.
    Keywords:  ADME; NRF2/KEAP1; cancer; drug discovery; health and wellbeing; molecular docking; molecular dynamics; natural compounds; oxidative stress
    DOI:  https://doi.org/10.3390/molecules28166003
  5. FASEB J. 2023 Sep;37(9): e23156
    Muscle p62 stimulates the expression of antioxidant proteins alleviating cancer cachexia.
    Mami Yamada, Eiji Warabi, Hisashi Oishi, Vitor A Lira, Mitsuharu Okutsu.
      Oxidative stress plays an important role in skeletal muscle atrophy during cancer cachexia, and more glycolytic muscles are preferentially affected. Sequestosome1/SQSTM1 (i.e., p62), particularly when phosphorylated at Ser 349 (Ser 351 in mice), competitively binds to the Kelch-like ECH-associated protein 1 (Keap1) activating Nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 then stimulates the transcription of antioxidant/electrophile-responsive elements in target genes. However, a potential role for p62 in the protection of muscle wasting in cachexia remains to be determined. Here, using the well-established cachexia-inducing model of Lewis Lung Carcinoma (LLC) in mice we demonstrate higher expression of antioxidant proteins (i.e., NQO1, HO-1, GSTM1, CuZnSOD, MnSOD, and EcSOD) in the more oxidative and cachexia resistant soleus muscle than in the more glycolytic and cachexia prone extensor digitorum longus muscle. This was accompanied by higher p62 (total and phosphorylated) and nuclear Nrf2 levels in the soleus, which were paralleled by higher expression of proteins known to either phosphorylate or promote p62 phosphorylation (i.e., NBR1, CK1, PKCδ, and TAK1). Muscle-specific p62 gain-of-function (i.e., in p62 mTg mice) activated Nrf2 nuclear translocation and increased the expression of multiple antioxidant proteins (i.e., CuZnSOD, MnSOD, EcSOD, NQO1, and GSTM1) in glycolytic muscles. Interestingly, skeletal muscle Nrf2 haplodeficiency blunted the increases of most of these proteins (i.e., CuZnSOD, EcSOD, and NQO1) suggesting that muscle p62 stimulates antioxidant protein expression also via additional, yet to be determined mechanisms. Of note, p62 gain-of-function mitigated glycolytic muscle wasting in LLC-affected mice. Collectively, our findings identify skeletal muscle p62 as a potential therapeutic target for cancer cachexia.
    Keywords:  Nrf2; SQSTM1/p62; antioxidants; muscle atrophy; oxidative stress; skeletal muscle
    DOI:  https://doi.org/10.1096/fj.202300349R
  6. Redox Biol. 2023 Aug 10. pii: S2213-2317(23)00246-X. [Epub ahead of print]66 102845
    A NRF2-induced secretory phenotype activates immune surveillance to remove irreparably damaged cells.
    Liam Baird, Keiko Taguchi, Anqi Zhang, Yushi Takahashi, Takafumi Suzuki, Thomas W Kensler, Masayuki Yamamoto.
      While it is well established that the KEAP1-NRF2 pathway regulates the main inducible cellular response to oxidative stress, this cytoprotective function of NRF2 could become deleterious to the host if it confers survival onto irreparably damaged cells. In this regard, we have found that in diseased states, NRF2 promotes the transcriptional activation of a specific subset of the senescence-associated secretory phenotype (SASP) gene program, which we have named the NRF2-induced secretory phenotype (NISP). In two models of hepatic disease using Pten::Keap1 and Keap1::Atg7 double knockout mice, we found that the NISP functions in the liver to recruit CCR2 expressing monocytes, which function as immune system effector cells to directly remove the damaged cells. Through activation of this immune surveillance pathway, in non-transformed cells, NRF2 functions as a tumour suppressor to mitigate the long-term survival of damaged cells which otherwise would be detrimental for host survival. This pathway represents the final stage of the oxidative stress response, as it allows cells to be safely removed if the macromolecular damage caused by the original stressor is so extensive that it is beyond the repair capacity of the cell.
    Keywords:  Efferocytosis; Immune surveillance; KEAP1; NFE2L2; NISP; NRF2; Oxidative stress; SASP; Senescence; Stress response
    DOI:  https://doi.org/10.1016/j.redox.2023.102845
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