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PSMC6 regulation of ovarian cancer cisplatin resistance unravels a new mode for proteasome targeting

  • 0Unit of Molecular Pharmacology, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
International Journal of Biological Sciences +

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March 14, 2025

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March 14, 2025

View abstract on PubMed

Summary

This summary is machine-generated.

PSMC6 protein levels correlate with poor ovarian carcinoma prognosis. Targeting PSMC6 may enhance cisplatin sensitivity in resistant ovarian cancer cells, offering a new therapeutic strategy.

Area Of Science

  • Oncology
  • Molecular Biology
  • Proteasome Biology

Background

  • Ovarian carcinoma presents a significant clinical challenge with a poor patient prognosis.
  • The role of the proteasome subunit PSMC6 in ovarian cancer progression and drug resistance remains largely unexplored.

Purpose Of The Study

  • To investigate the association between PSMC6 expression and ovarian carcinoma cell survival and cisplatin resistance.
  • To elucidate the underlying mechanisms by which PSMC6 influences ovarian cancer cell behavior.

Main Methods

  • CRISPR/Cas9 loss-of-function screening was employed to identify genes affecting cell survival.
  • PSMC6 expression levels were analyzed in ovarian cancer cell lines and correlated with clinical data.
  • Mechanistic studies involved PSMC6 knockdown, ubiquitinated protein analysis, ERK1/2 phosphorylation assays, and drug sensitivity testing.

Main Results

  • Elevated PSMC6 levels were observed in ovarian carcinoma cells compared to normal cells and associated with advanced tumor stages and reduced progression-free survival.
  • PSMC6 knockdown reduced cell growth and clonogenicity, induced ubiquitinated protein accumulation, and down-regulated ERK1/2 phosphorylation via DUSP6.
  • Silencing PSMC6 resensitized cisplatin-resistant ovarian cancer cells to cisplatin treatment, without affecting sensitivity to standard proteasome inhibitors.

Conclusions

  • PSMC6 is linked to ovarian carcinoma aggressiveness and poor prognosis, suggesting its potential as a diagnostic marker.
  • Targeting PSMC6, possibly through interference with proteasome ATPase activity, represents a novel therapeutic strategy to overcome cisplatin resistance in ovarian cancer.
  • Further research into PSMC6 biology could reveal new avenues for ovarian cancer treatment.

Keywords:

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