Title: Molecular effectors of autophagy and apoptosis in ER-photodamaged cells
Authors: Dewaele, Michael
Van Kelst, Sofie
Buytaert, Esther
de Witte, Peter
Martinet, Wim
Ferraro, Eliza
Cecconi, Franscesco
Mizushima, Noboru
Agostinis, Patrizia #
Issue Date: 2007
Conference: European Cell Death Organisation edition:15 location:Portoroz, Slovenia date:26-31 October 2007
Abstract: Molecular effectors of autophagy and apoptosis in ER-photodamaged cells

Michael Dewaele1, Sofie Van Kelst1, Esther Buytaert1, Peter de Witte1, Wim Martinet2,
Elisabetta Ferraro3, Francesco Cecconi3, Noboru Mizushima4 and Patrizia Agostinis1

1Dept. Molecular & Cell Biology, Faculty of Medicine, Catholic University of Leuven, and 2Division of Pharmacology, University of Antwerp, Belgium, 3Dulbecco Telethon Institute at the Department of Biology, University of Tor Vergata, Rome, Italy, 4Department of Physiology and Cell Biology Tokyo Medical and Dental University Graduate School and Faculty of Medicine, Tokyo, Japan

Photodynamic therapy (PDT) is an anticancer therapy utilizing cytotoxic reactive oxygen species (ROS) to kill the cancer cells1. Photodamage to the sarco(endo)plasmic Ca2+-ATPase (SERCA) pump, due to the local generation of 1O2 in the ER upon hypericin light irradiation, results in loss of ER Ca2+ homeostasis and is the most apical event causative for cell death in this paradigm2. Downstream of the ER-Ca2+ emptying, both caspase-dependent and -independent pathways are activated to ensure cell demise. Apoptosis is dependent on the availability of pro-apopototic Bax and Bak proteins, which are essential effectors of the mitochondrial membrane permeabilization and subsequent caspase activation2. Previous investigation has shown that cellular demise in murine embryonic fibroblasts (MEFs) doubly deficient for Bax/Bak (DKO) is due to the induction of an autophagic cell death pathway2. However, the exact role of autophagy in apoptosis-competent cells following PDT is not completely understood. To further elucidate the molecular players and the functional role of autophagy in PDT treated cells, we analyzed signalling events underlying cell death in wild type MEFs and in MEFs genetically deprived in mitochondrial apoptosis, such as in Bax/Bak (DKO) or Apaf-1-/- cells, as well as in apoptosis-competent MEFs in which autophagy can be turned off by knocking out essential autophagy genes (atg-genes).
In apoptosis-competent cells the induction of apoptotic cell death occurs concomitantly with the onset of autophagy, suggesting that both pathways are simultaneously propagated in response to ER photodamage. However, both the intensity and kinetics of the autophagic process are enhanced in the absence of caspase signalling, either caused by deficiency of pro-apoptotic Bax and Bak proteins or Apaf-1. Pharmacological inhibition of caspases in human cancer cells enhances PDT-induced autophagy, suggesting that once activated the caspase-signalling may deter autophagy progression. Under conditions of caspase inhibition photosensitized cells are fated to die with the phenotypic manifestations of autophagy. The knock-down of essential atg-genes in apoptosis-competent cells will be used to further define the exact role of autophagy induced by hypericin-PDT and to unravel the potential interplay between apoptosis and autophagy.

1Dolmans et al, (2003) Nat Rev Cancer 3:380-7
2Buytaert et al, (2006) FASEB J. 20:756-8
Description: Short Oral Communication
Based upon the abstract, a full scholarship (registration, traveling fee and living allowance) was awarded to attend this meeting
Publication status: accepted
KU Leuven publication type: IMa
Appears in Collections:Laboratory of Cell Death Research & Therapy
Laboratory of Dermatology
Laboratory for Pharmaceutical Biology (-)
Laboratory for Molecular Cancer Biology (VIB-KU Leuven Centre for Cancer Biology)
# (joint) last author

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