期刊
ONCOTARGET
卷 6, 期 39, 页码 41750-41765出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.6154
关键词
apoptosis; prohibitins; BCL-2 family members; mitochondria; cancer
资金
- Ministerio de Economia y Competitividad [SAF2013-41611-R]
- Red Tematica de Investigacion Cooperativa en Cancer (RTICC) [RD12/0036/0029]
- Instituto de Salud Carlos III
- European Regional Development Fund (ERDF)
- Fundacio Bosch i Gimpera [AVCRI-PPV022-08-Banco Santander]
- Consejo Interinstitucional de Ciencia y Tecnologia (CICYT) [CTQ2012-30930]
- AGAUR-Generalitat de Catalunya [2014SGR935, 2014SGR137]
- European Research Council (AdG) [233078]
- Ministerio de Economia y Competitividad
- European Research Council (ERC) [233078] Funding Source: European Research Council (ERC)
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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