A compound-based proteomic approach discloses 15-ketoatractyligenin methyl ester as a new PPARγ partial agonist with anti-proliferative ability

Maurizio Bruno, Antonio Lavecchia, Fabrizio Dal Piaz, Lina Sabatino, Vittorio Colantuoni, Ettore Novellino, Angelo Lupo, Carmen Cerchia, Nunziatina De Tommasi, Michele Vasaturo, Pamela Ziccardi, Lorenzo Fiengo

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Abstract

Proteomics based approaches are emerging as useful tools to identify the targets of bioactive compounds and elucidate their molecular mechanisms of action. Here, we applied a chemical proteomic strategy to identify the peroxisome proliferator-activated receptor γ (PPARγ) as a molecular target of the pro-apoptotic agent 15-ketoatractyligenin methyl ester (compound 1). We demonstrated that compound 1 interacts with PPARγ, forms a covalent bond with the thiol group of C285 and occupies the sub-pocket between helix H3 and the β-sheet of the ligand-binding domain (LBD) of the receptor by Surface Plasmon Resonance (SPR), mass spectrometry-based studies and docking experiments. 1 displayed partial agonism of PPARγ in cell-based transactivation assays and was found to inhibit the AKT pathway, as well as its downstream targets. Consistently, a selective PPARγ antagonist (GW9662) greatly reduced the anti-proliferative and pro-apoptotic effects of 1, providing the molecular basis of its action. Collectively, we identified 1 as a novel PPARγ partial agonist and elucidated its mode of action, paving the way for therapeutic strategies aimed at tailoring novel PPARγ ligands with reduced undesired harmful side effects.
Original languageEnglish
Pages (from-to)1-14
Number of pages14
JournalScientific Reports
Volume7
Publication statusPublished - 2017

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Peroxisome Proliferator-Activated Receptors
Proteomics
Esters
Ligands
Surface Plasmon Resonance
Sulfhydryl Compounds
Transcriptional Activation
Mass Spectrometry

All Science Journal Classification (ASJC) codes

  • General

Cite this

A compound-based proteomic approach discloses 15-ketoatractyligenin methyl ester as a new PPARγ partial agonist with anti-proliferative ability. / Bruno, Maurizio; Lavecchia, Antonio; Piaz, Fabrizio Dal; Sabatino, Lina; Colantuoni, Vittorio; Novellino, Ettore; Lupo, Angelo; Cerchia, Carmen; De Tommasi, Nunziatina; Vasaturo, Michele; Ziccardi, Pamela; Fiengo, Lorenzo.

In: Scientific Reports, Vol. 7, 2017, p. 1-14.

Research output: Contribution to journalArticle

Bruno, M, Lavecchia, A, Piaz, FD, Sabatino, L, Colantuoni, V, Novellino, E, Lupo, A, Cerchia, C, De Tommasi, N, Vasaturo, M, Ziccardi, P & Fiengo, L 2017, 'A compound-based proteomic approach discloses 15-ketoatractyligenin methyl ester as a new PPARγ partial agonist with anti-proliferative ability', Scientific Reports, vol. 7, pp. 1-14.
Bruno, Maurizio ; Lavecchia, Antonio ; Piaz, Fabrizio Dal ; Sabatino, Lina ; Colantuoni, Vittorio ; Novellino, Ettore ; Lupo, Angelo ; Cerchia, Carmen ; De Tommasi, Nunziatina ; Vasaturo, Michele ; Ziccardi, Pamela ; Fiengo, Lorenzo. / A compound-based proteomic approach discloses 15-ketoatractyligenin methyl ester as a new PPARγ partial agonist with anti-proliferative ability. In: Scientific Reports. 2017 ; Vol. 7. pp. 1-14.
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abstract = "Proteomics based approaches are emerging as useful tools to identify the targets of bioactive compounds and elucidate their molecular mechanisms of action. Here, we applied a chemical proteomic strategy to identify the peroxisome proliferator-activated receptor {\^I}³ (PPAR{\^I}³) as a molecular target of the pro-apoptotic agent 15-ketoatractyligenin methyl ester (compound 1). We demonstrated that compound 1 interacts with PPAR{\^I}³, forms a covalent bond with the thiol group of C285 and occupies the sub-pocket between helix H3 and the {\^I}²-sheet of the ligand-binding domain (LBD) of the receptor by Surface Plasmon Resonance (SPR), mass spectrometry-based studies and docking experiments. 1 displayed partial agonism of PPAR{\^I}³ in cell-based transactivation assays and was found to inhibit the AKT pathway, as well as its downstream targets. Consistently, a selective PPAR{\^I}³ antagonist (GW9662) greatly reduced the anti-proliferative and pro-apoptotic effects of 1, providing the molecular basis of its action. Collectively, we identified 1 as a novel PPAR{\^I}³ partial agonist and elucidated its mode of action, paving the way for therapeutic strategies aimed at tailoring novel PPAR{\^I}³ ligands with reduced undesired harmful side effects.",
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