A novel prohibitin-binding compound induces the mitochondrial apoptotic pathway through NOXA and BIM upregulation

We previously described diaryl trifluorothiazoline compound 1a (hereafter referred to as fluorizoline) as a first-in-class small molecule that induces p53-independent apoptosis in a wide range of tumor cell lines. Fluorizoline directly binds to prohibitin 1 and 2 (PHBs), two proteins involved in the...

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Detalles Bibliográficos
Autores: Moncunill Massaguer, Cristina, Saura-Esteller, José, Pérez-Perarnau, Alba, Palmeri, Claudia Mariela, Núñez-Vázquez, Sonia, Cosialls Castel, Ana Mª, González Gironés, Diana M., Pomares, Helena, Korwitz, Anne, Preciado Gallego, Sara, Albericio Palomera, Fernando, Lavilla Grífols, Rodolfo, Pons i Irazazábal, Gabriel, Langer, Thomas, Iglesias i Serret, Daniel, Gil i Santano, Joan
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2015
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:2445/96766
Acceso en línea:https://hdl.handle.net/2445/96766
Access Level:acceso abierto
Palabra clave:Càncer
Apoptosi
Mitocondris
Cancer
Apoptosis
Mitochondria
Descripción
Sumario:We previously described diaryl trifluorothiazoline compound 1a (hereafter referred to as fluorizoline) as a first-in-class small molecule that induces p53-independent apoptosis in a wide range of tumor cell lines. Fluorizoline directly binds to prohibitin 1 and 2 (PHBs), two proteins involved in the regulation of several cellular processes, including apoptosis. Here we demonstrate that fluorizoline-induced apoptosis is mediated by PHBs, as cells depleted of these proteins are highly resistant to fluorizoline treatment. In addition, BAX and BAK are necessary for fluorizoline-induced cytotoxic effects, thereby proving that apoptosis occurs through the intrinsic pathway. Expression analysis revealed that fluorizoline induced the upregulation of Noxa and Bim mRNA levels, which was not observed in PHB-depleted MEFs. Finally, Noxa-/-/Bim-/- MEFs and NOXA-downregulated HeLa cells were resistant to fluorizoline-induced apoptosis. All together, these findings show that fluorizoline requires PHBs to execute the mitochondrial apoptotic pathway.

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