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7-Bromoindirubin-3'-oxime uncovers a serine protease-mediated paradigm of necrotic cell death
Ribas i Fortuny, Judit; Yuste Mateos, Víctor J. (Víctor José); Garrofé Ochoa, Xènia; Meijer, Laurent; Esquerda Colell, Josep; Boix Torras, Jacint
The new 7-bromoindirubin-3′-oxime (7BIO) compound induces caspase-independent cell death in all cell lines tested to date. Irrespective of the cell line, a 25 μM treatment for 24 h is lethal for the entire cell population. In SH-SY5Y and Jurkat cells, 7BIO (25 μM) was found to collapse the mitochondrial transmembrane potential (ΔΨm) at only 2-3 h of treatment. Concomitantly mitochondria swelled, cristae disrupted and, after 9 h, external cell membranes ruptured. In addition, endoplasmic reticulum dilated and, unexpectedly, the acute cytoplasmic destruction yielded isolated nuclei with preserved morphology and DNA integrity. Furthermore, the process was independent of both Bax and Bak, since cell viability and ΔΨm decayed indistinguishably in double Bax−/−Bak−/− mouse embryonic fibroblasts (MEFs) and their wild type counterparts. Pharmacological inhibition of the mitochondrial permeability transition pore (MPTP) did not prevent 7BIO-induced ΔΨm loss in none of the aforementioned cell lines. Caspase-independent inducers of cell death like AIF (Apoptosis Inducing Factor), cathepsins and calpains were not involved. Only the chemical inhibitors of serine proteases and, particularly, AEBSF afforded a significant protection thus suggesting a process regulated by this type of enzymes. As far as we know, these features are quite unique once taken together. Therefore, we propose 7BIO is triggering a specific type of necrotic cell death. Finally, the cytotoxicity of 7BIO on apoptosis-resistant cells like double Bax−/−Bak−/− MEFs seems of great interest envisaging cancer therapy.
2008
Apoptosis
Autophagy
Necrosis
Indirubins
Bcl-2
Apoptosi
Necrosi
Autofàgia
Mort cel·lular
Apoptosis
Necrosis
Autophagy
Cell death
(c) Elsevier, 2008
Article
Elsevier
         

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