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

作者：Moncunill Massaguer Cristina; Saura Esteller Jose; Perez Perarnau Alba; Mariela Palmeri Claudia; Nunez Vazquez Sonia; Cosialls Ana M; Gonzalez Girones Diana M; Pomares Helena; Korwitz Anne; Preciado Sara; Albericio Fernando; Lavilla Rodolfo; Pons Gabriel; Langer Thomas; Iglesias Serret Daniel; Gil Joan

来源：Oncotarget, 2015, 6(39): 41750-41765.

DOI：10.18632/oncotarget.6154

• apoptosis
• prohibitins
• BCL-2 family members
• mitochondria
• cancer

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.

• 出版日期2015-12-8