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  1. Home
  3. A Novel Csn5/crt O-glcnac/er Stress Regulatory Axis In Platinum Resistance Of Epithelial Ovarian Cancer.
  1. Home
  3. A Novel Csn5/crt O-glcnac/er Stress Regulatory Axis In Platinum Resistance Of Epithelial Ovarian Cancer.

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A novel CSN5/CRT O-GlcNAc/ER stress regulatory axis in platinum resistance of epithelial ovarian cancer.

Tianqing Yan1,2, Xiaolu Ma1,2, Kaixia Zhou1,2

  • 1Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, No.270, Dong' An Road, Xuhui District, Shanghai 200032, China.

International Journal of Biological Sciences
|February 22, 2024

View abstract on PubMed

Summary
This summary is machine-generated.

High COP9 signalosome subunit 5 (CSN5) levels drive platinum resistance in epithelial ovarian cancer (EOC) by disrupting ER stress via O-GlcNAc modification of calreticulin (CRT). Inhibiting CSN5 restores platinum sensitivity.

Keywords:
COP9 signalosome subunit 5Calreticulin O-GlcNAcylationEndoplasmic reticulum stressOvarian cancerPlatinum resistance

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Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Elevated COP9 signalosome subunit 5 (CSN5) in epithelial ovarian cancer (EOC) correlates with poor prognosis and platinum resistance.
  • Mechanisms underlying CSN5's role in EOC platinum resistance remain largely undefined.

Purpose of the Study:

  • To elucidate the molecular mechanisms of CSN5-mediated platinum resistance in EOC.
  • To identify potential therapeutic targets for overcoming platinum resistance.

Main Methods:

  • RNA-sequencing to identify differentially expressed genes in platinum-resistant EOC cells with CSN5 knockdown.
  • O-GlcNAc proteomics to discover downstream modulators of CSN5.
  • In vitro and in vivo experiments to assess platinum sensitivity and validate findings.

Main Results:

  • CSN5 drives platinum resistance in EOC through aberrant O-GlcNAc modification and endoplasmic reticulum (ER) stress dysregulation.
  • CSN5 upregulates O-GlcNAc-calreticulin (CRT) at T346, inhibiting ER stress-induced apoptosis.
  • CSN5 inhibition or T346 modification blockade triggers Ca2+ disturbances, ER stress, mitochondrial dysfunction, and apoptosis, restoring platinum sensitivity.

Conclusions:

  • CSN5-mediated aberrant O-GlcNAc-CRT functions as a critical ER stress checkpoint, influencing cell fate in response to stress.
  • The CSN5/CRT O-GlcNAc/ER stress axis represents a novel therapeutic target for overcoming platinum resistance in EOC.