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De-differentiation confers multidrug resistance via noncanonical PERK-Nrf2 signaling

Catherine A Del Vecchio1, Yuxiong Feng1, Ethan S Sokol2

  • 1Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, United States of America.

Plos Biology
|September 10, 2014
PubMed

Insights

De-differentiated cancers develop multidrug resistance (MDR) through PERK-Nrf2 signaling, not oxidative stress. Targeting this pathway can re-sensitize resistant cancer cells to chemotherapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Stress Response

Background:

  • Recurrent malignant carcinomas often exhibit de-differentiation and multidrug resistance (MDR).
  • The mechanisms by which de-differentiated cancer cells acquire MDR, including upregulation of reactive oxygen species (ROS)-scavenging enzymes and drug efflux pumps, remain unclear.
  • Understanding the regulation of these genes during de-differentiation is crucial for overcoming therapeutic resistance.

Purpose of the Study:

  • To identify ROS-induced genes upregulated in de-differentiated cells independent of oxidative damage.
  • To elucidate the signaling pathway responsible for preactivating the Nrf2 transcription factor in de-differentiated cancer cells.
  • To investigate the therapeutic potential of targeting this pathway in drug-resistant cancers.

Main Methods:

  • Global transcriptional profiling to identify upregulated genes in de-differentiated cells.
  • Analysis of the Nrf2 transcription factor activation mechanism in differentiated versus de-differentiated cells.
  • Experimental validation in basal breast cancer cell lines and animal models.
  • Correlation analysis of PERK pathway signature with clinical data from patient tumor datasets.

Main Results:

  • Nrf2, a master regulator of oxidative stress response, is preactivated in de-differentiated cells via a noncanonical mechanism involving PERK-mediated phosphorylation, independent of oxidative damage.
  • This constitutive PERK-Nrf2 signaling confers MDR by reducing ROS levels and increasing drug efflux.
  • Inhibition of the PERK-Nrf2 pathway reversed MDR in therapy-resistant basal breast cancer models.
  • A PERK pathway signature in patient tumors strongly correlates with chemotherapy resistance, higher tumor grade, and poorer overall survival.

Conclusions:

  • De-differentiated cancer cells utilize a PERK-Nrf2 signaling axis to upregulate MDR genes, distinct from canonical oxidative stress responses.
  • Targeting the PERK-Nrf2 pathway presents a promising strategy to overcome chemotherapy resistance in de-differentiated and multidrug-resistant cancers.
  • This pathway serves as a potential biomarker for predicting treatment response and patient prognosis.

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