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USP2a alters chemotherapeutic response by modulating redox

B Benassi1, M Marani, M Loda

  • 1Unit of Radiation Biology and Human Health, ENEA-Casaccia, Rome, Italy.

Cell Death & Disease
|September 28, 2013
PubMed

Insights

The ubiquitin-specific protease 2a (USP2a) enzyme promotes chemoresistance in prostate cancer cells by increasing glutathione levels, which reduces oxidative stress and prevents apoptosis. Targeting c-Myc or miR-34b/c may reverse this drug resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Altered ubiquitination is a hallmark of cancer cells.
  • USP2a, a deubiquitinating enzyme, is overexpressed in prostate cancer and acts as an oncogene.
  • USP2a targets c-Myc through the miR-34b/c cluster, contributing to its oncogenic functions.

Purpose of the Study:

  • To investigate the role of USP2a in conferring drug resistance in prostate cancer cells.
  • To elucidate the molecular mechanisms by which USP2a mediates chemoresistance, focusing on oxidative stress and apoptosis.

Main Methods:

  • Overexpression of USP2a in immortalized and transformed prostate cells.
  • Treatment with chemotherapeutic agents (cisplatin, doxorubicin, taxanes).
  • Measurement of reactive oxygen species (ROS) production, mitochondrial membrane potential (ΔΨ), and apoptosis.
  • Assessment of glutathione (GSH) levels and c-Myc/miR-34b/c expression.

Main Results:

  • USP2a overexpression confers resistance to cisplatin, doxorubicin, and taxanes.
  • USP2a reduces drug-induced oxidative stress by decreasing ROS production and stabilizing mitochondrial membrane potential.
  • USP2a inhibits p38 activation and apoptosis.
  • USP2a increases intracellular GSH content via miR-34b/c-mediated c-Myc regulation, thereby interfering with oxidative stress cascades.

Conclusions:

  • USP2a plays a critical role in promoting chemoresistance in prostate cancer.
  • USP2a confers resistance by enhancing the antioxidant capacity through the GSH/c-Myc/miR-34b/c pathway.
  • Targeting c-Myc and/or miR-34b/c represents a potential strategy to overcome USP2a-mediated chemoresistance.

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