Inhibition of the PI3K/AKT/mTOR signaling promotes an M1 macrophage switch by repressing the ATF3-CXCL8 axis in Ewing sarcoma.

Autor: Palombo R; Laboratories of Molecular and Cellular Neurobiology, Molecular Neuroimmunology, and Resolution of Neuroinflammation, IRCCS Fondazione Santa Lucia, Via del Fosso di Fiorano, 64, 00143, Rome, Italy; University of Rome 'Foro Italico', Piazza Lauro de Bosis 6, 00135, Rome, Italy., Passacantilli I; Laboratories of Molecular and Cellular Neurobiology, Molecular Neuroimmunology, and Resolution of Neuroinflammation, IRCCS Fondazione Santa Lucia, Via del Fosso di Fiorano, 64, 00143, Rome, Italy., Terracciano F; Laboratories of Molecular and Cellular Neurobiology, Molecular Neuroimmunology, and Resolution of Neuroinflammation, IRCCS Fondazione Santa Lucia, Via del Fosso di Fiorano, 64, 00143, Rome, Italy., Capone A; Laboratories of Molecular and Cellular Neurobiology, Molecular Neuroimmunology, and Resolution of Neuroinflammation, IRCCS Fondazione Santa Lucia, Via del Fosso di Fiorano, 64, 00143, Rome, Italy., Matteocci A; Laboratories of Molecular and Cellular Neurobiology, Molecular Neuroimmunology, and Resolution of Neuroinflammation, IRCCS Fondazione Santa Lucia, Via del Fosso di Fiorano, 64, 00143, Rome, Italy., Tournier S; Plateforme Technologique IRSL UMS Saint-Louis US53 / UAR2030, Institut de Recherche Saint Louis, Université Paris Cité, France., Alberdi A; Plateforme Technologique IRSL UMS Saint-Louis US53 / UAR2030, Institut de Recherche Saint Louis, Université Paris Cité, France., Chiurchiù V; Laboratories of Molecular and Cellular Neurobiology, Molecular Neuroimmunology, and Resolution of Neuroinflammation, IRCCS Fondazione Santa Lucia, Via del Fosso di Fiorano, 64, 00143, Rome, Italy; Institute of Translational Pharmacology, CNR, Via del Fosso del Cavaliere, 100, 00133, Rome, Italy., Volpe E; Laboratories of Molecular and Cellular Neurobiology, Molecular Neuroimmunology, and Resolution of Neuroinflammation, IRCCS Fondazione Santa Lucia, Via del Fosso di Fiorano, 64, 00143, Rome, Italy., Paronetto MP; Laboratories of Molecular and Cellular Neurobiology, Molecular Neuroimmunology, and Resolution of Neuroinflammation, IRCCS Fondazione Santa Lucia, Via del Fosso di Fiorano, 64, 00143, Rome, Italy; University of Rome 'Foro Italico', Piazza Lauro de Bosis 6, 00135, Rome, Italy. Electronic address: mariapaola.paronetto@uniroma4.it.
Jazyk: angličtina
Zdroj: Cancer letters [Cancer Lett] 2023 Feb 28; Vol. 555, pp. 216042. Date of Electronic Publication: 2022 Dec 21.
DOI: 10.1016/j.canlet.2022.216042
Abstrakt: Ewing sarcomas are aggressive pediatric tumors of bone and soft tissues driven by in frame chromosomal translocations that yield fusion proteins guiding the oncogenic program. Promising alternative strategies to ameliorate current treatments involve inhibition of the PI3K/AKT/mTOR pathway. In this study, we identified the activating transcription factor 3 (ATF3) as an important mediator of the PI3K/AKT/mTOR pathway in Ewing sarcoma cells. ATF3 exerted its pro-tumoral activity through modulation of several chemokine-encoding genes, including CXCL8. The product of CXCL8, IL-8, acts as a pro-inflammatory chemokine critical for cancer progression and metastasis. We found that ATF3/IL-8 axis impacts macrophages populating the surrounding tumor microenvironment by promoting the M2 phenotype. Our study reveals valuable information on the PI3K/AKT/mTOR derived chemokine signaling in Ewing sarcoma cells: by promoting ATF3 and CXCL8 downregulation, inhibition of the PI3K/AKT/mTOR signaling promotes a proinflammatory response leading to upregulation of the protective anti-tumoral M1 macrophages.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2022 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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