The antiproliferative and proapoptotic effects of cladosporols A and B are related to their different binding mode as PPARγ ligands

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• 作者：Diana Zurlo^a ; ¹ ; Pamela Ziccardi^a ; ¹ ; Carolina Votino^a ; Tommaso Colangelo^a ; Carmen Cerchia^b ; Fabrizio Dal Piaz^c ; Sabrina Dallavalle^d ; Salvatore Moricca^e ; Ettore Novellino^b ; Antonio Lavecchia^b ; ^{antonio.lavecchia@unina.it" class="auth_mail" title="E-mail the corresponding author} ; Vittorio Colantuoni^a ; Angelo Lupo^a ; ^{lupo@unisannio.it" class="auth_mail" title="E-mail the corresponding author}
• 关键词：CAD ; caspase-activated deoxyribonuclease ; CRC ; colorectal cancer ; HR-ESI-MS ; high resolution electrospray ionization mass ; LBD ; ligand-binding domain ; MDA ; malondialdehyde ; NCoEx ; nuclear corepressor exchange factor ; PPARs ; peroxisome proliferator-activated receptors ; PBS ; phosphate saline buffer ; PPARγ ; peroxisome proliferator-activated receptor γ ; PPRE ; PPAR response element ; POX/PRODH ; proline oxidase/proline dehydrogenase ; RGZ ; rosiglitazone ; RSV ; Rous Sarcoma Virus ; RXR ; retinoid X receptor
• 刊名：Biochemical Pharmacology
• 出版年：2016
• 出版时间：15 May 2016
• 年：2016
• 卷：108
• 期：Complete
• 页码：22-35
• 全文大小：2854 K

文摘

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).