A novel prohibitin-binding compound induces the mitochondrial apoptotic pathway through NOXA and BIM upregulation
| Autor: | Rodolfo Lavilla, Claudia M. Palmeri, Gabriel Pons, Sonia Núñez-Vázquez, José Saura-Esteller, Helena Pomares, Sara Preciado, Alba Pérez-Perarnau, Daniel Iglesias-Serret, Ana M. Cosialls, Diana M. González-Gironès, Thomas Langer, Joan Gil, Anne Korwitz, Fernando Albericio, Cristina Moncunill-Massaguer |
|---|---|
| Přispěvatelé: | Universitat de Barcelona |
| Rok vydání: | 2015 |
| Předmět: |
prohibitins
Time Factors Repressor Antineoplastic Agents Apoptosis BCL-2 family members Mitochondrion Transfection Jurkat cells Mitocondris HeLa Jurkat Cells Mice Downregulation and upregulation hemic and lymphatic diseases Neoplasms Proto-Oncogene Proteins Tumor Cells Cultured Animals Humans cancer Prohibitin Càncer Cancer biology Bcl-2-Like Protein 11 Dose-Response Relationship Drug Apoptosi Membrane Proteins Fibroblasts biology.organism_classification Molecular biology 3. Good health Cell biology Mitochondria Up-Regulation Repressor Proteins Thiazoles Oncology Proto-Oncogene Proteins c-bcl-2 Drug Resistance Neoplasm Signal transduction Apoptosis Regulatory Proteins Reactive Oxygen Species HT29 Cells HeLa Cells Signal Transduction Research Paper |
| Zdroj: | Oncotarget Recercat. Dipósit de la Recerca de Catalunya instname Dipòsit Digital de la UB Universidad de Barcelona |
| ISSN: | 1949-2553 |
| Popis: | // Cristina Moncunill-Massaguer 1 , Jose Saura-Esteller 1 , Alba Perez-Perarnau 1 , Claudia Mariela Palmeri 1 , Sonia Nunez-Vazquez 1 , Ana M. Cosialls 1 , Diana M. Gonzalez-Girones 1 , Helena Pomares 1 , Anne Korwitz 2 , Sara Preciado 3 , Fernando Albericio 3,4,5 , Rodolfo Lavilla 3,6 , Gabriel Pons 1 , Thomas Langer 2 , Daniel Iglesias-Serret 1,* and Joan Gil 1,* 1 Departament de Ciencies Fisiologiques II, Universitat de Barcelona-Institut d’Investigacio Biomedica 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|