Oncotarget

Research Papers:

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

Cristina Moncunill-Massaguer, José Saura-Esteller, Alba Pérez-Perarnau, Claudia Mariela Palmeri, Sonia Núñez-Vázquez, Ana M. Cosialls, Diana M. González-Gironès, Helena Pomares, Anne Korwitz, Sara Preciado, Fernando Albericio, Rodolfo Lavilla, Gabriel Pons, Thomas Langer, Daniel Iglesias-Serret and Joan Gil _

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2015; 6:41750-41765. https://doi.org/10.18632/oncotarget.6154

Metrics: PDF 2669 views  |   HTML 3851 views  |   ?  


Abstract

Cristina Moncunill-Massaguer1, José Saura-Esteller1, Alba Pérez-Perarnau1, Claudia Mariela Palmeri1, Sonia Núñez-Vázquez1, Ana M. Cosialls1, Diana M. González-Gironès1, Helena Pomares1, Anne Korwitz2, Sara Preciado3, Fernando Albericio3,4,5, Rodolfo Lavilla3,6, Gabriel Pons1, Thomas Langer2, Daniel Iglesias-Serret1,* and Joan Gil1,*

1 Departament de Ciències Fisiològiques II, Universitat de Barcelona-Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), L’Hospitalet de Llobregat, Catalunya, Spain

2 Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany

3 Barcelona Science Park and CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, Barcelona, Spain

4 Institute for Research in Biomedicine Barcelona, Barcelona, Spain

5 Department of Organic Chemistry, University of Barcelona, Barcelona, Spain

6 Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, Barcelona, Spain

* These authors share senior co-authorship

Correspondence to:

Joan Gil, email:

Keywords: apoptosis, prohibitins, BCL-2 family members, mitochondria, cancer

Received: April 29, 2015 Accepted: September 30, 2015 Published: October 19, 2015

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 6154