bims-redobi Biomed News
on Redox Biology
Issue of 2024‒09‒15
seven papers selected by
Vanesa Cepas López, Candiolo Cancer Institute
  1. Simultaneous Targeting of NQO1 and SOD1 Eradicates Breast Cancer Stem Cells via Mitochondrial Futile Redox Cycling.
  2. ALDH1A3 is the switch that determines the balance of ALDH+ and CD24-CD44+ cancer stem cells, EMT-MET, and glucose metabolism in breast cancer.
  3. Defining Cytokine Responsive and Non-responsive human β-cells.
  4. Blocking tumor-intrinsic MNK1 kinase restricts metabolic adaptation and diminishes liver metastasis.
  5. To Elucidate the Effective Role of Small Molecule Regulated lncRNAs in the Tumour Microenvironment in Immunotherapy.
  6. 4-Hydroxynonenal Promotes Colorectal Cancer Progression through Regulating Cancer Stem Cell Fate.
  7. Hydrogen sulfide as a therapeutic agent in renal ischemia-reperfusion injury: Mechanistic insights and clinical potential.
  1. Cancer Res. 2024 Sep 12.
    Simultaneous Targeting of NQO1 and SOD1 Eradicates Breast Cancer Stem Cells via Mitochondrial Futile Redox Cycling.
    Ming Luo, Na Shen, Li Shang, Zeng Fang, Ying Xin, Yuxi Ma, Min Du, Yuan Yuan, Chenchen Hu, Yun Tang, Jing Huang, Wei Wei, Myung Ryul Lee, Paul J Hergenrother, Max S Wicha.
      Triple negative breast cancer (TNBC) contains the highest proportion of cancer stem-like cells (CSCs), which display intrinsic resistance to currently available cancer therapies. This therapeutic resistance is partially mediated by an antioxidant defense coordinated by the transcription factor NRF2 and its downstream targets including NQO1. Here, we identified the antioxidant enzymes NQO1 and SOD1 as therapeutic vulnerabilities of ALDH+ epithelial-like CSCs and CD24-/loCD44+/hi mesenchymal-like CSCs in TNBC. Effective targeting of these CSC states was achieved by utilizing IB-DNQ, a potent and specific NQO1-bioactivatable futile redox cycling molecule, which generated large amounts of reactive oxygen species (ROS) including superoxide and hydrogen peroxide. Furthermore, the CSC killing effect was specifically enhanced by genetic or pharmacological inhibition of SOD1, a copper-containing superoxide dismutase highly expressed in TNBC. Mechanistically, a significant portion of NQO1 resided in the mitochondrial intermembrane space, catalyzing futile redox cycling from IB-DNQ to generate high levels of mitochondrial superoxide, and SOD1 inhibition markedly potentiated this effect resulting in mitochondrial oxidative injury, cytochrome c release, and activation of the caspase 3-mediated apoptotic pathway. Treatment with IB-DNQ alone or together with SOD1 inhibition effectively suppressed tumor growth, metastasis, and tumor-initiating potential in xenograft models of TNBC expressing different levels of NQO1. This futile oxidant-generating strategy, which targets CSCs across the epithelial-mesenchymal continuum, could be a promising therapeutic approach for treating TNBC patients.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-0800
  2. Oncogene. 2024 Sep 09.
    ALDH1A3 is the switch that determines the balance of ALDH+ and CD24-CD44+ cancer stem cells, EMT-MET, and glucose metabolism in breast cancer.
    Wasundara Fernando, Brianne M Cruickshank, Raj Pranap Arun, Maya R MacLean, Hannah F Cahill, Fiorella Morales-Quintanilla, Cheryl A Dean, Marie-Claire D Wasson, Margaret L Dahn, Krysta M Coyle, Olivia L Walker, Melanie R Power Coombs, Paola Marcato.
      Plasticity is an inherent feature of cancer stem cells (CSCs) and regulates the balance of key processes required at different stages of breast cancer progression, including epithelial-to-mesenchymal transition (EMT) versus mesenchymal-to-epithelial transition (MET), and glycolysis versus oxidative phosphorylation. Understanding the key factors that regulate the switch between these processes could lead to novel therapeutic strategies that limit tumor progression. We found that aldehyde dehydrogenase 1A3 (ALDH1A3) regulates these cancer-promoting processes and the abundance of the two distinct breast CSC populations defined by high ALDH activity and CD24-CD44+ cell surface expression. While ALDH1A3 increases ALDH+ breast cancer cells, it inversely suppresses the CD24-CD44+ population by retinoic acid signaling-mediated gene expression changes. This switch in CSC populations induced by ALDH1A3 was paired with decreased migration but increased invasion and an intermediate EMT phenotype. We also demonstrate that ALDH1A3 increases oxidative phosphorylation and decreases glycolysis and reactive oxygen species (ROS). The effects of ALDH1A3 reduction were countered with the glycolysis inhibitor 2-deoxy-D-glucose (2DG). In cell culture and tumor xenograft models, 2DG suppresses the increase in the CD24-CD44+ population and ROS induced by ALDH1A3 knockdown. Combined inhibition of ALDH1A3 and glycolysis best reduces breast tumor growth and tumor-initiating cells, suggesting that the combination of targeting ALDH1A3 and glycolysis has therapeutic potential for limiting CSCs and tumor progression. Together, these findings identify ALDH1A3 as a key regulator of processes required for breast cancer progression and depletion of ALDH1A3 makes breast cancer cells more susceptible to glycolysis inhibition.
    DOI:  https://doi.org/10.1038/s41388-024-03156-4
  3. Function (Oxf). 2024 Sep 09. pii: zqae039. [Epub ahead of print]
    Defining Cytokine Responsive and Non-responsive human β-cells.
    Samuel B Stephens.
      
    Keywords:  beta-cells; cytokines; inflammation; islets; single-cell RNA-seq
    DOI:  https://doi.org/10.1093/function/zqae039
  4. Sci Adv. 2024 Sep 13. 10(37): eadi7673
    Blocking tumor-intrinsic MNK1 kinase restricts metabolic adaptation and diminishes liver metastasis.
    Samuel E J Preston, Michael S Dahabieh, Raúl Ernesto Flores González, Christophe Gonçalves, Vincent R Richard, Matthew Leibovitch, Eleanor Dakin, Theodore Papadopoulos, Carolina Lopez Naranjo, Paige A McCallum, Fan Huang, Natascha Gagnon, Stephanie Perrino, René P Zahedi, Christoph H Borchers, Russell G Jones, Pnina Brodt, Wilson H Miller, Sonia V Del Rincón.
      Dysregulation of the mitogen-activated protein kinase interacting kinases 1/2 (MNK1/2)-eukaryotic initiation factor 4E (eIF4E) signaling axis promotes breast cancer progression. MNK1 is known to influence cancer stem cells (CSCs); self-renewing populations that support metastasis, recurrence, and chemotherapeutic resistance, making them a clinically relevant target. The precise function of MNK1 in regulating CSCs, however, remains unexplored. Here, we generated MNK1 knockout cancer cell lines, resulting in diminished CSC properties in vitro and slowed tumor growth in vivo. Using a multiomics approach, we functionally demonstrated that loss of MNK1 restricts tumor cell metabolic adaptation by reducing glycolysis and increasing dependence on oxidative phosphorylation. Furthermore, MNK1-null breast and pancreatic tumor cells demonstrated suppressed metastasis to the liver, but not the lung. Analysis of The Cancer Genome Atlas (TCGA) data from breast cancer patients validated the positive correlation between MNK1 and glycolytic enzyme protein expression. This study defines metabolic perturbations as a previously unknown consequence of targeting MNK1/2, which may be therapeutically exploited.
    DOI:  https://doi.org/10.1126/sciadv.adi7673
  5. Curr Med Chem. 2024 Sep 09.
    To Elucidate the Effective Role of Small Molecule Regulated lncRNAs in the Tumour Microenvironment in Immunotherapy.
    Ahmed Saad Abdullah Al-Qaysi, Ayşe Hale Alkan, İbrahim Gadashli, Demet Cansaran-Duman.
      The tumour microenvironment is a complex ecosystem comprising tumour cells, and cancer stem cells, and support cells that facilitate cancer growth and escape from treatment. Cancer immunotherapy focuses on immunological pathways such as PD-1/PD-L1 and CTLA-4 to target cancer stem cells via immune cells. Small molecules, immune checkpoint inhibitors, are employed to impede tumour growth by targeting cellular mediators in the cell cycle and tumour microenvironment. Long non-coding RNAs (lncRNAs) affect the growth, development, motility, and differentiation of cancer cells by regulating gene expression and are therefore considered important biomarkers. Small molecules demonstrate their effects on gene expression and behaviour of cancer cells by inducing lncRNAs. This relationship between lncRNAs and small molecules is of great importance in terms of their impact on cancer and the tumour microenvironment. The evaluation of this communication in clinical trials is of critical importance for the development of therapeutic strategies. This review provides a detailed description of the role of lncRNAs and small molecules in the tumour microenvironment and their relationship with cancer stem cells. Thus, the potential of controlling lncRNAs and using anti-cancer small molecules in TME to improve the efficacy of cancer therapy was evaluated.
    Keywords:  Tumour microenvironment; cancer immunotherapy; lncRNAs; small molecules
    DOI:  https://doi.org/10.2174/0109298673318929240829065611
  6. Antioxid Redox Signal. 2024 Sep 12.
    4-Hydroxynonenal Promotes Colorectal Cancer Progression through Regulating Cancer Stem Cell Fate.
    Xu Huang, Lin Huang, Chunhua Ma, Mingyang Hong, Lili Xu, Yuanyuan Ju, Haibo Li, Yilang Wang, Xingmin Wang.
      AIMS: Tumor microenvironment (TME) plays a crucial role in sustaining cancer stem cells (CSCs). 4-hydroxynonenal (4-HNE) is abundantly present in the TME of colorectal cancer (CRC). However, the contribution of 4-HNE to CSCs and cancer progression remains unclear. This study aimed to investigate the impact of 4-HNE on the regulation of CSC fate and tumor progression.METHODS: Human CRC cells were exposed to 4-HNE, and CSC signaling was analyzed using quantitative real-time PCR, immunofluorescent staining, fluorescence-activated cell sorting, and bioinformatic analysis. Tumor-promoting role of 4-HNE was confirmed using a xenograft model.
    RESULTS: Exposure of CRC cells to 4-HNE activated non-canonical Hedgehog (HH) signaling and homologous recombination repair (HRR) pathways in LGR5+ CSCs. Furthermore, blocking HH signaling led to a significant increase in the expression of γH2AX, indicating that 4-HNE induces double-stranded DNA breaks (DSBs) and simultaneously activates HH signaling to protect CSCs from 4-HNE-induced damage via the HRR pathway. Additionally, 4-HNE treatment increased the population of LGR5+ CSCs and promoted asymmetric division in these cells, leading to enhanced self-renewal and differentiation. Notably, 4-HNE also promoted xenograft tumor growth and activated CSC signaling in vivo.
    INNOVATION AND CONCLUSION: These findings demonstrate that 4-HNE, as a signaling inducer in the TME, activates the non-canonical HH pathway to shield CSCs from oxidative damage, enhances the proliferation and asymmetric division of LGR5+ CSCs, and thereby facilitates tumor growth. These novel insights shed light on the regulation of CSC fate within the oxidative TME, offering potential implications for understanding and targeting CSCs for CRC therapy.
    DOI:  https://doi.org/10.1089/ars.2023.0530
  7. Nephrology (Carlton). 2024 Sep 10.
    Hydrogen sulfide as a therapeutic agent in renal ischemia-reperfusion injury: Mechanistic insights and clinical potential.
    Chih-Ning Chen, Vin-Cent Wu.
      
    DOI:  https://doi.org/10.1111/nep.14384
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