Glutathione overproduction mediates lymphoma initiating cells survival and has a sex-dependent effect on lymphomagenesis.

Autor: H-Alcántara A; Cell-cell communication and inflammation Unit, Centro de Biología Molecular Severo Ochoa (CBM), CSIC-UAM, Madrid, Spain., Kourani O; Cell-cell communication and inflammation Unit, Centro de Biología Molecular Severo Ochoa (CBM), CSIC-UAM, Madrid, Spain., Marcos-Jiménez A; Immunology Department, Instituto de Investigación Sanitaria Princesa, Hospital Universitario de la Princesa, Madrid, Spain., Martínez-Núñez P; Cell-cell communication and inflammation Unit, Centro de Biología Molecular Severo Ochoa (CBM), CSIC-UAM, Madrid, Spain., Herranz-Martín E; Cell-cell communication and inflammation Unit, Centro de Biología Molecular Severo Ochoa (CBM), CSIC-UAM, Madrid, Spain., Fuentes P; Immune System Development and Function Unit, CBM, CSIC-UAM, Madrid, Spain., Toribio ML; Immune System Development and Function Unit, CBM, CSIC-UAM, Madrid, Spain., Muñoz-Calleja C; Immunology Department, Instituto de Investigación Sanitaria Princesa, Hospital Universitario de la Princesa, Madrid, Spain.; Centro de Investigación Biomédica en Red en Enfermedades Infecciosas (CIBERINFEC) Madrid, Madrid, Spain.; Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain., Iglesias T; Department of Neurological Diseases and Aging, Instituto de Investigaciones Biomédicas Sols-Morreale, CSIC-UAM, Madrid, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) Madrid, Madrid, Spain., Campanero MR; Cell-cell communication and inflammation Unit, Centro de Biología Molecular Severo Ochoa (CBM), CSIC-UAM, Madrid, Spain. mcampanero@cbm.csic.es.; Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain. mcampanero@cbm.csic.es.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2024 Jul 27; Vol. 15 (7), pp. 534. Date of Electronic Publication: 2024 Jul 27.
DOI: 10.1038/s41419-024-06923-z
Abstrakt: Lymphoid tumor patients often exhibit resistance to standard therapies or experience relapse post-remission. Relapse is driven by Tumor Initiating Cells (TICs), a subset of tumor cells capable of regrowing the tumor and highly resistant to therapy. Growing cells in 3D gels is a method to discern tumorigenic cells because it strongly correlates with tumorigenicity. The finding that TICs, rather than differentiated tumor cells, grow in 3D gels offers a unique opportunity to unveil TIC-specific signaling pathways and therapeutic targets common to various cancer types. Here, we show that culturing lymphoid cells in 3D gels triggers reactive oxygen species (ROS) production, leading to non-tumor lymphoid cell death while enabling the survival and proliferation of a subset of lymphoma/leukemia cells, TICs or TIC-like cells. Treatment with the antioxidant N-acetylcysteine inhibits this lethality and promotes the growth of primary non-tumor lymphoid cells in 3D gels. A subset of lymphoma cells, characterized by an increased abundance of the antioxidant glutathione, escape ROS-induced lethality, a response not seen in non-tumor cells. Reducing glutathione production in lymphoma cells, either through pharmacological inhibition of glutamate cysteine ligase (GCL), the enzyme catalyzing the rate-limiting step in glutathione biosynthesis, or via knockdown of GCLC, the GCL catalytic subunit, sharply decreased cell growth in 3D gels and xenografts. Tumor cells from B-cell lymphoma/leukemia patients and λ-MYC mice, a B-cell lymphoma mouse model, overproduce glutathione. Importantly, pharmacological GCL inhibition hindered lymphoma growth in female λ-MYC mice, suggesting that this treatment holds promise as a therapeutic strategy for female lymphoma/leukemia patients.
(© 2024. The Author(s).)
Databáze: MEDLINE
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