Cancer cell radioresistance is the primary cause of the decreased curability of non-small cell lung cancer (NSCLC) observed in patients receiving definitive radiotherapy (RT). Following RT, a set of microenvironmental stress responses is triggered, including cell senescence. However, cell senescence is often ignored in designing effective strategies to resolve cancer cell radioresistance. Herein, we identify the senescence-like characteristics of cancer-associated fibroblasts (CAFs) after RT and clarify the formidable ability of senescence-like CAFs in promoting NSCLC cell proliferation and radioresistance through the JAK/STAT pathway. Specific induction of senescence-like CAF apoptosis using FOXO4-DRI, a FOXO4-p53-interfering peptide, resulted in remarkable effects on radiosensitizing NSCLC cells in vitro and in vivo. In addition, in this study, we also uncovered an obvious therapeutic effect of FOXO4-DRI on alleviating radiation-induced pulmonary fibrosis (RIPF) by targeting senescence-like fibroblasts in vivo. In conclusion, by targeting senescence, we offer a strategy that simultaneously decreases radioresistance of NSCLC and the incidence of RIPF.
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http://dx.doi.org/10.1172/jci.insight.146334 | DOI Listing |
Neurobiol Dis
November 2024
Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of medicine, Baltimore, MD, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address:
Autophagy
January 2025
Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
Mitophagy, the selective autophagic clearance of damaged mitochondria, is considered vital for maintaining mitochondrial quality and cellular homeostasis; however, its molecular mechanisms, particularly under basal conditions, and its role in cellular physiology remain poorly characterized. We recently demonstrated that basal mitophagy is a key feature of primary human cells and is downregulated by immortalization, suggesting its dependence on the primary cell state. Mechanistically, we demonstrated that the PINK1-PRKN-SQSTM1 pathway regulates basal mitophagy, with SQSTM1 sensing superoxide-enriched mitochondria through its redox-sensitive cysteine residues, which mediate SQSTM1 oligomerization and mitophagy activation.
View Article and Find Full Text PDFAging (Albany NY)
October 2024
Sorbonne Université, CNRS UMR 8256 Biological Adaptation and Ageing (B2A), INSERM U1164, Institut de Biologie Paris Seine (IBPS), Paris 75005, France.
The accumulation of senescent cells, characterized by a senescence-associated secretory phenotype (SASP), contributes to chronic inflammation and age-related diseases (ARD). During aging, macrophages can adopt a senescent-like phenotype and an altered function, which promotes senescent cell accumulation. In the context of aging and ARD, controlling the resolution of the inflammatory response and preventing chronic inflammation, especially by targeting macrophages, must be a priority.
View Article and Find Full Text PDFFront Cell Dev Biol
June 2024
Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM) et Institut du Cancer de Montréal, Montreal, QC, Canada.
Malignant Melanoma that resists immunotherapy remains the deadliest form of skin cancer owing to poor clinically lasting responses. Alternative like genotoxic or targeted chemotherapy trigger various cancer cell fates after treatment including cell death and senescence. Senescent cells can be eliminated using senolytic drugs and we hypothesize that the targeted elimination of therapy-induced senescent melanoma cells could complement both conventional and immunotherapies.
View Article and Find Full Text PDFJ Dent Res
July 2024
Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Most of the elderly population is afflicted by periodontal diseases, creating a health burden worldwide. Cellular senescence is one of the hallmarks of aging and associated with several chronic comorbidities. Senescent cells produce a variety of deleterious secretions, collectively termed the (SASP).
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