Abstract
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.
Highlights
Resistance to cell death is one of the hallmarks of cancer development, and it compromises the efficacy of conventional anti-cancer agents [1]
Fluorizoline requires the presence of prohibitins in order to induce apoptosis We previously reported that fluorizoline (Figure 1a) binds to PHB1 and PHB2 [2]
PHBs are interdependent at the protein level, loss of PHB2 leads to the degradation of PHB1 [9, 10]
Summary
Resistance to cell death is one of the hallmarks of cancer development, and it compromises the efficacy of conventional anti-cancer agents [1]. The requirement of PHBs for cell proliferation strongly indicates a potential role in cancer progression [4, 11, 12, 22, 35] Along this line, overexpression of PHB1 results in a higher resistance to apoptosis in different types of cancer cells, while downregulation of PHBs renders cancer cells more susceptible to pro-apoptotic insults [11, 21, 29, 36], suggesting a pro-tumorigenic role of PHBs. In view of the pleiotropic functions of PHBs, these proteins emerge as highly interesting targets for the development of novel treatments for cancer [11, 29, 37]. We further dissect the mechanism by which fluorizoline induces apoptosis and demonstrate that this compound requires PHBs to increase Noxa and Bim expression and to trigger the mitochondrial apoptotic pathway
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