7-Bromoindirubin-3'-oxime uncovers a serine protease-mediated paradigm of necrotic cell death
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 mitochond...
| Autores: | , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión aceptada para publicación |
| Fecha de publicación: | 2008 |
| País: | España |
| Institución: | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| Repositorio: | Recercat. Dipósit de la Recerca de Catalunya |
| OAI Identifier: | oai:recercat.cat:10459.1/48092 |
| Acceso en línea: | https://doi.org/10.1016/j.bcp.2008.03.023 http://hdl.handle.net/10459.1/48092 |
| Access Level: | acceso abierto |
| Palabra clave: | Apoptosis Autophagy Necrosis Indirubins Bcl-2 Apoptosi Necrosi Autofàgia Mort cel·lular Cell death |
| Sumario: | 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. |
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