Title: Concomitant induction of apoptosis and autophagy in ER-photodamaged cells after hypericine-PDT
Authors: Dewaele, Michael
Van Kelst, Sofie
Buytaert, Esther
de Witte, Peter
Martinet, Wim
Agostinis, Patrizia #
Issue Date: 2007
Conference: Interuniversity Attraction Pole 6/18 location:Liege, Belgium date:19 June 2007
Abstract: Concomitant induction of apoptosis and autophagy in ER-photodamaged cells after hypericine-PDT

M. Dewaele1, S. Van Kelst1, E. Buytaert1, P. de Witte2, W. Martinet3 and P. Agostinis1

1Department of Molecular Cell Biology, Faculty of Medicine, Catholic University of Leuven, Belgium
2Lab for Pharmaceutical Biology, Catholic University of Leuven, Belgium
3Division of Pharmacology, University of Antwerp, Belgium

Photodynamic therapy (PDT) is a new paradigm of anticancer therapy based on the induction of cell death by the generation of cytotoxic reactive oxygen species1. Photodamage to the sarco(endo)plasmic Ca2+-ATPase (SERCA) pump and the subsequent loss of Ca2+ homeostasis, due to the selective accumulation of the photosensitizer hypericin in the ER, is the most apical molecular event causative for cell death2. 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 pro-apopototic Bax and Bak proteins, which are essential effectors of the mitochondrial membrane permeabilization and subsequent caspase activation2. Although previous investigation has shown cellular demise in murine embryonic fibroblasts (MEFs) doubly deficient for Bax/Bak (DKO) to be due to the induction of an autophagic cell death pathway2, the exact role of autophagy in both apoptosis-competent and –incompetent cells following hypericin-photosensitization is not completely understood. To shed more light into 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 the conditional knock-out of the essential autophagy gene Atg5.
In apoptosis-competent cells the induction of caspase signalling and apoptosis 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/Bak proteins or Apaf-1. Moreover, 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. Interestingly, the conditional knock-out of Atg5 does not only prevent the induction of autophagy but appears also to reduce apoptotic cell death, suggesting that following ER-photodamage apoptosis and autophagy are regulated by common proximal effectors. We are further investigating the molecular mechanism by which Atg5 may connect both pathways and evaluating the role of autophagy and autophagic cell death in our paradigm.

1Dolmans et al, (2003) Nat Rev Cancer 3:380-7
2Buytaert et al, (2006) FASEB J. 20:756-8
Publication status: accepted
KU Leuven publication type: AMa
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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