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Role of endoplasmic reticulum depletion and multidomain proapoptotic BAX and BAK proteins in shaping cell death after hypericin‐mediated photodynamic therapy
Author(s) -
Buytaert Esther,
Callewaert Geert,
Hendrickx Nico,
Scorrano Luca,
Hartmann Dieter,
Missiaen Ludwig,
Vandenheede Jackie R.,
Heirman Ingeborg,
Grooten Johan,
Agostinis Patrizia
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.05-4305fje
Subject(s) - endoplasmic reticulum , autophagy , programmed cell death , microbiology and biotechnology , apoptosis , unfolded protein response , homeostasis , intracellular , hypericin , photodynamic therapy , cell , chemistry , mitochondrion , biology , biochemistry , pharmacology , organic chemistry
Both the commitment event and the modality of cell death in photodynamic therapy (PDT) remain poorly defined. We report that PDT with endoplasmic reticulum (ER)‐associating hypericin leads to an immediate loss of SERCA2 protein levels, causing disruption of Ca 2+ homeostasis and cell death. Protection of SERCA2 protein rescues ER‐Ca 2+ levels and prevents cell death, suggesting that SERCA2 photodestruction with consequent incapability of the ER to maintain intracellular Ca 2+ homeostasis is causal to cell killing. Apoptosis is rapidly initiated after ER‐Ca 2+ depletion and strictly requires the BAX/BAK gateway at the mitochondria. Bax −/− Bak −/− double‐knockout (DKO) cells are protected from apoptosis but undergo autophagy‐associated cell death as revealed by electron microscopy and biochemical analysis. Autophagy inhibitors, but not caspase antagonists, significantly reduce death of DKO cells, suggesting that sustained autophagy is lethal. Thus, following ER photodamage and consequent disruption of Ca 2+ homeostasis, BAX and BAK proteins model PDT‐mediated cell killing, which is executed through apoptosis in their presence or via an autophagic pathway in their absence.