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A novel prohibitin-binding compound induces the mitochondrial apoptotic pathway through NOXA and BIM upregulation
Moncunill Massaguer, Cristina; Saura-Esteller, José; Pérez-Perarnau, Alba; Palmeri, Claudia Mariela; Núñez-Vázquez, Sonia; Cosialls Castel, Ana Mª; González-Gironès, Diana Maria; Pomares, Helena; Korwitz, Anne; Preciado Gallego, Sara; Albericio Palomera, Fernando; Lavilla Grífols, Rodolfo; Pons i Irazazábal, Gabriel; Langer, Thomas; Iglesias Serret, Daniel; Gil i Santano, Joan
Universitat de Barcelona
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.
Càncer
Apoptosi
Mitocondris
Cancer
Apoptosis
Mitochondria
cc-by (c) Moncunill-Massaguer,Cristina et al., 2015
http://creativecommons.org/licenses/by/3.0/es
Article
info:eu-repo/semantics/publishedVersion
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