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Animals
Antineoplastic Agents/*pharmacology
Apoptosis/*drug effects
Apoptosis Regulatory Proteins/genetics/*metabolism
Bcl-2-Like Protein 11
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm
Fibroblasts/*drug effects/metabolism/pathology
HT29 Cells
HeLa Cells
Humans
Jurkat Cells
Membrane Proteins/genetics/*metabolism
Mice
Mitochondria/*drug effects/metabolism/pathology
Neoplasms/*drug therapy/genetics/metabolism/pathology
Proto-Oncogene Proteins/genetics/*metabolism
Proto-Oncogene Proteins c-bcl-2/genetics/*metabolism
Reactive Oxygen Species/metabolism
Repressor Proteins/genetics/*metabolism
Signal Transduction/drug effects
Thiazoles/*pharmacology
Time Factors
Transfection
Tumor Cells, Cultured
Up-Regulation
BCL-2 family members
apoptosis
cancer
mitochondria
prohibitins
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.
