European Cell Death Organisation, Euroconference on Apoptosis edition:14 location:Chia, Italy date:29 September - 04 October
Autophagic cell death by photodamage to the endoplasmic reticulum
Michael Dewaele, Esther Buytaert and Patrizia Agostinis
Dept. Molecular & Cell Biology, Faculty of Medicine, Catholic University of Leuven, Belgium
Photodynamic therapy (PDT) is a paradigm of anticancer therapy utilizing the generation of reactive oxygen species to kill the cancer cells1. Recently, we have identified the photodamage to the sarco(endo)plasmic-reticulum Ca2+-ATPase (SERCA) pump and consequent loss in the ER-Ca2+ homeostasis as the most apical molecular events leading to cell death in hypericin-photosensitized cells2. Downstream of the ER-Ca2+ emptying, both caspase-dependent and -independent pathways are activated to ensure cell demise. The induction of apoptosis as a cell death modality is dependent on the availability of proapopototic Bax and Bak proteins, which are essential effectors of the mitochondrial outer membrane permeabilization (MOMP) and subsequent caspase activation. Antagonists of autophagy protect Bax-/-/Bak-/- murine embryonic fibroblasts (MEF) cells from photokilling, whereas they do not prevent apoptotic cell death in the wild type MEF. On the other hand, caspase-3/-7 inhibitors partially protect wild type cells from PDT-mediated apoptosis while they do not affect autophagic cell death in the photosensitized Bax-/-/Bak-/- MEF, thus arguing that these two pathways are concurrently promoted and do not actively suppress each other. Preliminary examination of apoptotic and autophagy parameters in ER-photodamaged cancer cells suggests that these processes are initiated jointly although with different kinetics and that the inability of the pan-caspase inhibitor zVAD-fmk to rescue the cells from photokilling may be due to enduring autophagy. In conclusion, while Bax/Bak-dependent MOMP is the preferred cell death route in hypericin-photosensitized cells ensuring the fast caspase-dependent disassembly of the cells, the concomitant induction of autophagy builds up a default cell death pathway, which is utilized to kill cells with defects in the apoptotic pathway. Although the exact contribution of autophagy as a tumor suppression mechanism in vivo should be carefully evaluated, the ability of hypericin-PDT to engage different lethal routes of cell destruction, encourages further studies to establish the molecular mechanisms turning autophagy into a cell death pathway in cancer cells exposed to this anticancer strategy.
1Dolmans et al., (2003) Nat Rev Cancer 3:380-7
2Buytaert et al., (2006) FASEB J. 20:756-8
Based on the abstract, a full scholarship (registration, traveling fee and living allowance) was rewarded for this conference