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Autophagy pathways activated in response to PDT contribute to cell resistance against ROS damage

Michael Dewaele1, Wim Martinet, Noemí Rubio

  • 1Cell Death Research and Therapy Laboratory, Department of Molecular Cell Biology, Faculty of Medicine, Katholieke Universiteit Leuven, Leuven, Belgium.

Journal of Cellular and Molecular Medicine
|July 15, 2010
PubMed

Insights

Photodynamic therapy (PDT) induces cell death by generating reactive oxygen species (ROS). This study reveals autophagy

Area of Science:

  • Cellular Stress Responses
  • Cancer Biology
  • Autophagy Research

Background:

  • Reactive oxygen species (ROS) play a dual role in cell death, instigating both apoptosis and autophagy.
  • The interplay between ROS-induced apoptosis and autophagy remains incompletely understood.
  • Photodynamic therapy (PDT) utilizes ROS for cancer treatment, necessitating a clearer grasp of these cellular pathways.

Purpose of the Study:

  • To investigate the role of autophagy in cancer cell response to PDT-induced ROS.
  • To elucidate the specific autophagy pathways involved in cellular defense against PDT.
  • To understand the relationship between macroautophagy (MA) and chaperone-mediated autophagy (CMA) during PDT.

Main Methods:

  • Utilized photodynamic therapy (PDT) to generate reactive oxygen species (ROS) in cancer and normal cells.
  • Manipulated autophagy pathways using genetic (Atg5 knockdown, Atg(-/-) cells) and pharmacological (3-methyladenine) approaches.
  • Assessed cellular responses including apoptosis, protein oxidation, and endoplasmic reticulum (ER) stress.
  • Investigated the Akt-mTOR signaling pathway and antioxidant enzyme glutathione peroxidase-4 (GPx4) expression.

Main Results:

  • PDT induced Akt-mTOR pathway down-regulation and stimulated macroautophagy (MA) in cells.
  • Overexpression of GPx4 reversed mTOR down-regulation, inhibited MA, and reduced apoptosis.
  • MA attenuation increased oxidatively damaged proteins and enhanced apoptosis, indicating a cytoprotective role.
  • Genetic loss of MA paradoxically improved oxidized protein clearance but reduced photokilling.
  • Chaperone-mediated autophagy (CMA) up-regulation compensated for MA loss, conferring resistance to PDT.
  • CMA-deficient cells showed increased sensitivity to PDT but resistance to ER stress.

Conclusions:

  • Macroautophagy (MA) plays a cytoprotective role in response to PDT-induced oxidative stress.
  • Chaperone-mediated autophagy (CMA) acts as the primary defense mechanism against PDT-induced phototoxicity.
  • Autophagy pathways are recruited in a stress-specific manner to protect cells, with CMA being dominant against PDT.
  • Understanding these distinct autophagy roles is crucial for optimizing PDT efficacy in cancer therapy.

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