The International Cell Death Society, Symposium on Cell Death in Infectious Diseases and Cancer location:Johannesburg, South-Africa date:5-8 June
Stimulation of autophagy pathways improve cancer cell survival after oxidative stress
Michael Dewaele1, Wim Martinet2, Ana Maria Cuervo3 and Patrizia Agostinis1
1Dept. Molecular Cell Biology, Catholic University of Leuven, Belgium
2Div. of Pharmacology, University of Antwerp, Belgium
3Dept. Anatomy and Structural Biology, Albert Einstein College of Medicin, New York
Photodynamic therapy (PDT) is a new and innovative anticancer therapy utilizing cytotoxic ROS produced after irradiation of a photosensitizer with visible light, to kill the cancer cells. Light activation of the ER-associated photosensitizer hypericin results in the rapid loss of ER Ca2+ homeostasis which leads to ER-stress and subsequent mitochondrial apoptosis. In this study we show that the generation of apoptotic doses of ROS by PDT results in the rapid shutdown of the Akt-mTOR pathway followed by the induction of macroautophagy. Pharmacological inhibition of macroautophagy with 3-methyladenine or siRNA-mediated knockdown of Atg5 in human cancer cells suppresses macroautophagy and increases the apoptotic fraction of PDT-treated cells, defining macroautophagy as a cell survival mechanism in this paradigm of oxidative stress. Intriguingly, chronic inhibition of macroautophagy by the knock-out of Atg5 does not only inhibit macroautophagy but also hampers caspase activation in response to PDT in both normal or transformed MEFs. This cytoprotective effect could be attributed to an increased capacity of Atg5-deficient cells to remove oxidized proteins as compared to their wild type counterparts. We have identified chaperone-mediated autophagy (CMA) as the lysosomal pathway for the efficient clearance of oxidized and toxic proteins in PDT-treated cells, which is upregulated in cells chronically deprived of macroautophagy. CMA-deficient cells are extremely sensitized to PDT-induced cell death, thus suggesting that this pathway functions as a first line defence against ROS damage. This study further suggests that pharmacological inhibition of autophagy mechanisms in ROS-damaged cancer cells may becomes an attractive intervention to improve the clinical application of PDT and possibly other anticancer modalities utilizing ROS as primary damaging agents.