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

Oncotarget. 2015 Dec 8;6(39):41750-65. doi: 10.18632/oncotarget.6154.

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.

Keywords: BCL-2 family members; apoptosis; cancer; mitochondria; prohibitins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • BCL2L11 protein, human
  • Bcl-2-Like Protein 11
  • Bcl2l11 protein, mouse
  • Membrane Proteins
  • PHB protein, human
  • PMAIP1 protein, human
  • Pmaip1 protein, mouse
  • Prohibitins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Reactive Oxygen Species
  • Repressor Proteins
  • Thiazoles