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First published online 17 November 2009
doi: 10.1242/jcs.055772

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Inhibition of the ER Ca²⁺ pump forces multidrug-resistant cells deficient in Bak and Bax into necrosis

Katja Janssen^1,2, Sibylle Horn^1,2, Mathis T. Niemann^1,2, Peter T. Daniel³, Klaus Schulze-Osthoff^1,2,* and Ute Fischer^1,2,*,

¹ Interfaculty Institute for Biochemistry, University of Tübingen, 72076 Tübingen, Germany
² Institute of Molecular Medicine, Heinrich-Heine-University, 40225 Düsseldorf, Germany
³ Department of Hematology, Oncology and Tumor Immunology, University Medical Center Charité, 13125 Berlin, Germany

Author for correspondence (ute.fischer{at}uni-tuebingen.de)

Accepted 29 September 2009

Tumor cells deficient in the proapoptotic proteins Bak and Bax are resistant to chemotherapeutic drugs. Here, we demonstrate that murine embryonic fibroblasts deficient for both Bak and Bax are, however, efficiently killed by thapsigargin, a specific inhibitor of ER Ca²⁺ pumps that induces ER stress by depleting ER Ca²⁺ stores. In the presence of Bak and Bax, thapsigargin eliminates cells by release of mitochondrial cytochrome c and subsequent caspase activation, which leads to the proteolytic inactivation of the molecular necrosis switch PARP-1 and results in apoptosis. By contrast, in the absence of Bak and Bax, a failure to activate caspases results in PARP-1-mediated ATP depletion. The subsequent necrosis is not prevented by autophagy as an alternative energy source. Moreover, in cells deficient for both Bak and Bax, thapsigargin induces permanent mitochondrial damage by Ca²⁺ overload, permeability transition and membrane rupture. Thus, even though deficiency in Bak and Bax protects these cells against apoptosis, it does not compromise necrosis induced by SERCA inhibitors. Importantly, thapsigargin induces caspase-independent cell death also in colon and prostate carcinoma cells deficient in Bak and Bax expression. Therefore, targeted application of ER stressors such as thapsigargin might be a promising approach for the treatment of Bak- and Bax-deficient, drug-resistant tumors.

Key words: ER stress, PARP, SERCA, Bak, Bax, Necrosis, Multidrug resistance, UPR, Autophagy, Ire1

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