|ITEM METADATA RECORD
|Title: ||Hypericin-photodynamic therapy mediated oxidative ER-stress as a trigger for apoptotic and autophagic pathways|
|Authors: ||Dewaele, Michael|
Agostinis, Patrizia #
|Issue Date: ||2009 |
|Conference: ||Oncogorum date:4 February|
|Abstract: ||Hypericin-photodynamic therapy mediated oxidative ER-stress as a trigger for apoptotic and autophagic pathways
Michael Dewaele1, Esther Buytaert1, Wim Martinet2, and Patrizia Agostinis1
1Dept. Molecular Cell Biology, Faculty of Medicine, Catholic University of Leuven, Belgium 2Division of Pharmacology, University of Antwerp, Belgium.
Photodynamic therapy (PDT) is a new and innovative anticancer therapy utilizing cytotoxic reactive oxygen species (ROS) produced after irradiation of a photosensitizer with visible light, to kill the cancer cells1. Light activation of the ER-associated photosensitizer hypericin causes immediate photooxidative damage to the SERCA pump, due to the local generation of 1O2., This event results in the rapid loss of ER Ca2+ homeostasis which leads to ER-stress and a subsequent stress-response, triggering both apoptotic cell death and macroautophagy (autophagy). While a previous study indicated an involvement of autophagy in the execution of apoptosis-incompetent Bax/Bak double knock-out MEFs2, the exact role of PDT-induced autophagy in apoptosis-competent cells remains largely unclear. In this study we show that in apoptosis-competent cells, the induction of apoptotic cell death occurs concomitantly with autophagy, suggesting that both pathways are simultaneously propagated in response to PDT-mediated ER stress. To study the functional role of autophagy in apoptosis-competent cells we used MEFs conditionally expressing the essential atg-gene Atg5. Interestingly, in these MEFs, the knock-out of Atg5, does not only inhibit autophagy but also hampers the release of cytochrome c and caspase-activation in response to PDT. Intriguingly, Atg5 deficient cells exhibit, despite the absence of autophagy, an increased capacity to remove oxidative damaged proteins as compared to their wild type counterparts. On the other hand, pharmacological inhibition of autophagy with 3-methyladenine or siRNA knockdown of Atg5 in the human cervical carcinoma HeLa, also suppresses autophagy but increases the apoptotic fraction of PDT-treated cells, due to a hampered removal of oxidized proteins.
While the pharmacological inhibition of autophagy after PDT seems a powerful combinatorial approach for the treatment of cancer, these data also point at a complex level of cross-communication between apoptosis and autophagy and suggest that compensatory and protective mechanisms exist in cells in which autophagy has been permanently knocked down. We are currently investigating the involvement of the ubiquitin-proteasome system (UPS) and chaperone-mediated autophagy (CMA) as compensatory mechanisms, potentially involved in the enhanced clearance of photomodified proteins of autophagy-deficient MEFs.
1Buytaert et al, (2007) BBA 1776:86-107
2Buytaert et al, (2006) FASEB J. 20:756-758
|Publication status: ||accepted|
|KU Leuven publication type: ||AMa|
|Appears in Collections:||Laboratory of Cell Death Research & Therapy|
Laboratory for Molecular Cancer Biology
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