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Clusterin Deficiency Promotes Cellular Senescence in Human Astrocytes
P. Sultana, O. Honc, Z. Hodny, J. Novotny
Language English Country United States
Document type Journal Article
Grant support
SVV-260683
Univerzita Karlova v Praze
LX22NPO5102
European Union - Next Generation EU
- MeSH
- Astrocytes * metabolism pathology MeSH
- Clusterin * metabolism genetics MeSH
- Humans MeSH
- Membrane Potential, Mitochondrial * physiology MeSH
- Mitochondria * metabolism MeSH
- Cell Line, Tumor MeSH
- Oxidative Stress physiology MeSH
- Oxidative Phosphorylation MeSH
- DNA Damage MeSH
- Cell Proliferation * MeSH
- Reactive Oxygen Species metabolism MeSH
- Cellular Senescence * physiology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
The glycoprotein clusterin (CLU) is involved in cell proliferation and DNA damage repair and is highly expressed in tumor cells. Here, we aimed to investigate the effects of CLU dysregulation on two human astrocytic cell lines: CCF-STTG1 astrocytoma cells and SV-40 immortalized normal human astrocytes. We observed that suppression of CLU expression by RNA interference inhibited cell proliferation, triggered the DNA damage response, and resulted in cellular senescence in both cell types tested. To further investigate the underlying mechanism behind these changes, we measured reactive oxygen species, assessed mitochondrial function, and determined selected markers of the senescence-associated secretory phenotype. Our results suggest that CLU deficiency triggers oxidative stress-mediated cellular senescence associated with pronounced alterations in mitochondrial membrane potential, mitochondrial mass, and expression levels of OXPHOS complex I, II, III and IV, indicating mitochondrial dysfunction. This report shows the important role of CLU in cell cycle maintenance in astrocytes. Based on these data, targeting CLU may serve as a potential therapeutic approach valuable for treating gliomas.
References provided by Crossref.org
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- $a The glycoprotein clusterin (CLU) is involved in cell proliferation and DNA damage repair and is highly expressed in tumor cells. Here, we aimed to investigate the effects of CLU dysregulation on two human astrocytic cell lines: CCF-STTG1 astrocytoma cells and SV-40 immortalized normal human astrocytes. We observed that suppression of CLU expression by RNA interference inhibited cell proliferation, triggered the DNA damage response, and resulted in cellular senescence in both cell types tested. To further investigate the underlying mechanism behind these changes, we measured reactive oxygen species, assessed mitochondrial function, and determined selected markers of the senescence-associated secretory phenotype. Our results suggest that CLU deficiency triggers oxidative stress-mediated cellular senescence associated with pronounced alterations in mitochondrial membrane potential, mitochondrial mass, and expression levels of OXPHOS complex I, II, III and IV, indicating mitochondrial dysfunction. This report shows the important role of CLU in cell cycle maintenance in astrocytes. Based on these data, targeting CLU may serve as a potential therapeutic approach valuable for treating gliomas.
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