Author: Zheng, Yi ; Wells, Susanne I ; Sertorio, Mathieu ; Brons, Stephan ; Nowrouzi, Ali ; Salomonis, Nathan ; Akbarpour, Mahdi ; Ionascu, Dan ; Mascia, Anthony ; Chetal, Kashish ; Abdollahi, Amir ; McCauley, Shelby ; Köthe, Andreas ; Kupneski, Taylor ; Debus, Jürgen ; Perentesis, John P

BACKGROUND AND PURPOSEKnowledge of biological responses to proton therapy (PT) in comparison to X-ray remains in its infancy. Identification of PT specific molecular signals is an important opportunity for the discovery of biomarkers and synergistic drugs to advance clinical application. Since PT is used for the treatment of lymphoma, we report here transcriptomic responses of lymphoma cell lines to PT vs X-ray and identify potential therapeutic targets.MATERIALS AND METHODSTwo lymphoma cell lines of human (BL41) and murine (J3D) origin were irradiated by X-ray and PT. Differential transcriptome regulation was quantified by RNA sequencing for each radiation type at 12 hours post irradiation. Gene-set enrichment analysis revealed deregulated molecular pathways and putative targets for lymphoma cell sensitization to PT.RESULTSTranscriptomic gene set enrichment analyses uncovered pathways that contribute to the unfolded protein response (UPR) and mitochondrial transport. Functional validation at multiple time points demonstrated increased UPR activation and decreased protein translation, perhaps due to increased oxidative stress and oxidative protein damage after PT. PPARgamma was identified as a potential regulator of the PT transcriptomic response. Inhibition of PPARgamma by two compounds, T0070907 and SR2595, sensitized lymphoma cells to PT.CONCLUSIONSProton vs X-ray radiation leads to the transcriptional regulation of a specific subset of genes in line with diminished protein translation and UPR activation that may be due to oxidative stress. This study demonstrates that different radiation qualities trigger distinct cellular responses in lymphoma cells, and identifies PPARgamma inhibition as a potential strategy for the sensitization of lymphoma to PT.

01 Dec 2017·Molecular & Cellular Proteomics

Unique Interactome Network Signatures for Peroxisome Proliferator-activated Receptor Gamma (PPARγ) Modulation by Functional Selective Ligands

Article

Author: Griffin, Patrick R ; Lam, Vinh Q ; Zheng, Jie

The nuclear receptor PPARγ regulates adipogenesis and plays a central role in lipid and glucose homeostasis, and is the molecular target of the glitazones (TZDs), therapeutics used to treat insulin resistance and type-2 diabetes (T2D). Although the TZDs, which are PPARγ agonists, demonstrated robust clinical efficacy in T2D, their use has been hampered by an array of untoward side effects. Paradoxically, partial agonists (e.g. MRL24), antagonists (e.g. SR1664), and inverse agonists (e.g. SR10171 and SR2595), possess similar insulin-sensitizing efficacy as the TZDs in obese diabetic mice. Given the unique pharmacology of these modulators, we sought to identify the components of the PPARγ transcriptional complex that is regulated by these ligands. To achieve this, we employed subcellular fractionation of adipocytes combined with either trapping of the receptor complex on biotinylated DNA oligonucleotide, or classical immunoprecipitation. Tandem mass spectrometry analysis revealed unique, partially overlapping, compound- and subcellular compartment-specific complexes. Components of these interactomes are putative coregulators of PPARγ. Interestingly, complexes isolated in the cytosol contain sets of proteins involve in cellular assembly and extracellular matrix. Furthermore, the interactome observed for cytosolic non-DNA bound receptor was distinct from that observed from nuclear chromatin associated PPARγ, suggesting cellular compartment-specific roles for this receptor.

Nature CommunicationsQ1 · CROSS-FIELD

Pharmacological repression of PPARγ promotes osteogenesis

Q1 · CROSS-FIELD

ArticleOA

Author: Park, HaJeung ; Garcia-Ordonez, Ruben ; Khan, Tanya M ; Asteian, Alice ; Marciano, David P ; Novick, Scott J ; Kamenecka, Theodore M ; Kuruvilla, Dana S ; Phinney, Donald G ; Griffin, Patrick R ; Bruning, John B ; Kojetin, Douglas J ; Hughes, Travis S ; Boregowda, Siddaraju V ; Corzo, Cesar A

The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is the master regulator of adipogenesis and the pharmacological target of the thiazolidinedione (TZD) class of insulin sensitizers. Activation of PPARγ by TZDs promotes adipogenesis at the expense of osteoblast formation, contributing to their associated adverse effects on bone. Recently, we reported the development of PPARγ antagonist SR1664, designed to block the obesity-induced phosphorylation of serine 273 (S273) in the absence of classical agonism, to derive insulin-sensitizing efficacy with improved therapeutic index. Here we identify the structural mechanism by which SR1664 actively antagonizes PPARγ, and extend these findings to develop the inverse agonist SR2595. Treatment of isolated bone marrow-derived mesenchymal stem cells with SR2595 promotes induction of osteogenic differentiation. Together these results identify the structural determinants of ligand-mediated PPARγ repression, and suggest a therapeutic approach to promote bone formation.

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Indication	Highest Phase	Country/Location	Organization	Date
Osteoporosis	Discovery	US	The Scripps Research Institute	-

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