The antiproliferative and proapoptotic effects of cladosporols A and B are related to their different binding mode as PPARγ ligands
| Autor: | Salvatore Moricca, Ettore Novellino, Vittorio Colantuoni, Carmen Cerchia, Pamela Ziccardi, Sabrina Dallavalle, Antonio Lavecchia, Tommaso Colangelo, Fabrizio Dal Piaz, Angelo Lupo, Diana Zurlo, Carolina Votino |
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| Přispěvatelé: | Zurlo, Diana, Ziccardi, Pamela, Votino, Carolina, Colangelo, Tommaso, Cerchia, Carmen, Dal Piaz, Fabrizio, Dallavalle, Sabrina, Moricca, Salvatore, Novellino, Ettore, Lavecchia, Antonio, Colantuoni, Vittorio, Lupo, Angelo |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Protein Conformation Peroxisome proliferator-activated receptor Apoptosis Naphthols Ligands Biochemistry Docking Transactivation 0302 clinical medicine Anilides chemistry.chemical_classification Tumor Stereoisomerism Cell biology Cladosporols Colorectal cancer cells Full and partial PPARγ agonists Antineoplastic Agents Cell Line Tumor Cell Proliferation Cyclin-Dependent Kinase Inhibitor p21 Drug Partial Agonism G1 Phase Cell Cycle Checkpoints HEK293 Cells Humans Molecular Docking Simulation Oxidative Stress PPAR gamma Protein Binding Structure-Activity Relationship Transcriptional Activation Pharmacology 030220 oncology & carcinogenesis Retinoid X receptor Biology Partial agonist Cell Line 03 medical and health sciences Structure–activity relationship Cell growth HEK 293 cells Apoptosi Cladosporol 030104 developmental biology chemistry Docking (molecular) Colorectal cancer cell |
| Popis: | Cladosporols are secondary metabolites from Cladosporium tenuissimum characterized for their ability to control cell proliferation. We previously showed that cladosporol A inhibits proliferation of human colon cancer cells through a PPARγ-mediated modulation of gene expression. In this work, we investigated cladosporol B, an oxidate form of cladosporol A, and demonstrate that it is more efficient in inhibiting HT-29 cell proliferation due to a robust G0/G1-phase arrest and p21(waf1/cip1) overexpression. Cladosporol B acts as a PPARγ partial agonist with lower affinity and reduced transactivation potential in transient transfections as compared to the full agonists cladosporol A and rosiglitazone. Site-specific PPARγ mutants and surface plasmon resonance (SPR) experiments confirm these conclusions. Cladosporol B in addition displays a sustained proapoptotic activity also validated by p21(waf1/cip1) expression analysis in the presence of the selective PPARγ inhibitor GW9662. In the DMSO/H2O system, cladosporols A and B are unstable and convert to the ring-opened compounds 2A and 2B. Finally, docking experiments provide the structural basis for full and partial PPARγ agonism of 2A and 2B, respectively. In summary, we report here, for the first time, the structural characteristics of the binding of cladosporols, two natural molecules, to PPARγ. The binding of compound 2B is endowed with a lower transactivation potential, higher antiproliferative and proapoptotic activity than the two full agonists as compound 2A and rosiglitazone (RGZ). |
| Databáze: | OpenAIRE |
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