Title: Autophagy pathways activated in response to PDT contribute to cell resistance against ROS damage
Authors: Dewaele, Michael
Martinet, Wim
Rubio Romero, Noemí
Verfaillie, Tom
de Witte, Peter A
Piette, Jacques
Agostinis, Patrizia # ×
Issue Date: 2011
Publisher: Wiley-Blackwell Publishing Ltd.
Series Title: Journal of Cellular and Molecular Medicine vol:15 pages:1402-1414
Abstract: Reactive oxygen species (ROS) concurrently instigate apoptosis and autophagy pathways, but the link between these processes remains unclear. Since cytotoxic ROS formation is exploited in anticancer therapy, such as in photodynamic therapy (PDT), a better understanding of the complex interplay between autophagy and apoptosis is urgently required. Previously, we reported that ROS generated by PDT with an endoplasmic reticulum(ER)-associated sensitizer leads to loss of ER-Ca2+ homeostasis, ER stress and apoptosis. Here we show that PDT prompted Akt-mTOR pathway down-regulation and stimulated macroautophagy in cancer and normal cells. Overexpression of the antioxidant enzyme glutathione peroxidase-4 reversed mTOR down-regulation and blocked macroautophagy progression and apoptosis. Attenuating macroautophagy using Atg5 knockdown or 3-methyladenine, reduced clearance of oxidatively damaged proteins and increased apoptosis, thus revealing a cytoprotective role of macroautophagy in PDT. Paradoxically, genetic loss of macroautophagy improved clearance of oxidized proteins and reduced photokilling. We found that up-regulation of chaperone-mediated autophagy (CMA) in unstressed Atg5-/- cells compensated for macroautophagy loss and increased cellular resistance to PDT. CMA-deficient cells were significantly sensitized to photokilling but were protected against the ER stressor thapsigargin. These results disclose a stress-specific recruitment of autophagy pathways with cytoprotective function and unravel CMA as the dominant defense mechanism against PDT.
ISSN: 1582-4934
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Cell Death Research & Therapy
Laboratory for Pharmaceutical Biology (-)
Laboratory for Molecular Cancer Biology
× corresponding author
# (joint) last author

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