Clusterin Deficiency Promotes Cellular Senescence in Human Astrocytes.

in Molecular neurobiology by Pinky Sultana, Ondrej Honc, Zdenek Hodny, Jiri Novotny

TLDR

  • The study reveals the important role of clusterin in cell cycle maintenance in astrocytes and suggests that targeting CLU may be a potential therapeutic approach for treating gliomas.

Abstract

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.

Overview

  • The study investigates the effects of clusterin (CLU) dysregulation on two human astrocytic cell lines: CCF-STTG1 astrocytoma cells and SV-40 immortalized normal human astrocytes.
  • The researchers aimed to understand the role of CLU in cell proliferation, DNA damage repair, and its expression in tumor cells.
  • The study aims to determine if targeting CLU could be a potential therapeutic approach for treating gliomas.

Comparative Analysis & Findings

  • Suppression of CLU expression by RNA interference inhibited cell proliferation and triggered the DNA damage response in both cell types tested.
  • CLU deficiency resulted in cellular senescence in both cell types, accompanied by pronounced alterations in mitochondrial membrane potential, mitochondrial mass, and expression levels of OXPHOS complex I, II, III, and IV.
  • The study suggests that CLU deficiency triggers oxidative stress-mediated cellular senescence associated with mitochondrial dysfunction.

Implications and Future Directions

  • The study suggests that targeting CLU may serve as a potential therapeutic approach for treating gliomas.
  • Future studies could explore the underlying mechanisms behind CLU-mediated senescence and mitochondrial dysfunction.
  • ELucidating the role of CLU in astrocyte cell cycle maintenance could lead to the development of novel therapeutic strategies for glioma treatment.
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