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Double-stranded RNA-dependent protein kinase regulates the motility of breast cancer cells

Mei Xu1, Gang Chen, Siying Wang

  • 1Department of Internal Medicine, University of Kentucky College of Medicine, Lexington, Kentucky, United States of America.

Plos One
|November 1, 2012
PubMed

Insights

Activating double-stranded RNA (dsRNA)-dependent protein kinase (PKR) suppresses breast cancer cell motility. This pathway involves regulating p38 MAPK, LIMK, and cofilin, offering potential anti-tumor strategies.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Double-stranded RNA (dsRNA)-dependent protein kinase (PKR) is an interferon-induced kinase crucial for antiviral responses.
  • PKR exhibits pro-apoptotic and anti-proliferative effects, making it a target for anti-tumor strategies.
  • While PKR is overexpressed in breast cancer, its specific role in cancer cell behavior, particularly motility, remains unclear.

Purpose of the Study:

  • To investigate the role of PKR in regulating breast cancer cell motility and migration.
  • To elucidate the molecular mechanisms by which PKR influences cell movement.

Main Methods:

  • Activation of PKR using a synthesized dsRNA (PIC) in breast cancer cell lines (BT474, MDA-MB231, SKBR3).
  • Assessment of cell motility, migration, cell viability, and actin cytoskeleton organization.
  • Analysis of signaling pathways including p38 MAPK, MK2, LIMK1, and cofilin phosphorylation.
  • Utilized PKR inhibitors and siRNA for mechanistic validation.

Main Results:

  • PIC significantly decreased breast cancer cell motility and migration without affecting viability.
  • PIC inhibited cell membrane ruffling, lamellipodia formation, and induced actin cytoskeleton reorganization.
  • PKR activation led to the phosphorylation and inactivation of cofilin via the p38 MAPK/MK2/LIMK1 pathway.
  • These effects were reversed by a selective PKR inhibitor, confirming PKR's role.

Conclusions:

  • PKR activation suppresses breast cancer cell motility and migration.
  • The mechanism involves the regulation of the p38 MAPK/MK2/LIMK1/cofilin pathway.
  • Targeting PKR represents a potential therapeutic strategy for reducing breast cancer cell aggressiveness.

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