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Peroxisome proliferator-activated receptor gamma as a theragnostic target for mesenchymal-type glioblastoma patients.

ABSTRACT: Glioblastomas (GBMs) are characterized by four subtypes, proneural (PN), neural, classical, and mesenchymal (MES) GBMs, and they all have distinct activated signaling pathways. Among the subtypes, PN and MES GBMs show mutually exclusive genetic signatures, and the MES phenotype is, in general, believed to be associated with more aggressive features of GBM: tumor recurrence and drug resistance. Therefore, targeting MES GBMs would improve the overall prognosis of patients with fatal tumors. In this study, we propose peroxisome proliferator-activated receptor gamma (PPAR?) as a potential diagnostic and prognostic biomarker as well as therapeutic target for MES GBM; we used multiple approaches to assess PPAR?, including biostatistics analysis and assessment of preclinical studies. First, we found that PPAR? was exclusively expressed in MES glioblastoma stem cells (GSCs), and ligand activation of endogenous PPAR? suppressed cell growth and stemness in MES GSCs. Further in vivo studies involving orthotopic and heterotopic xenograft mouse models confirmed the therapeutic efficacy of targeting PPAR?; compared to control mice, those that received ligand treatment exhibited longer survival as well as decreased tumor burden. Mechanistically, PPAR? activation suppressed proneural-mesenchymal transition (PMT) by inhibiting the STAT3 signaling pathway. Biostatistical analysis using The Cancer Genomics Atlas (TCGA, n?=?206) and REMBRANDT (n?=?329) revealed that PPAR? upregulation is linked to poor overall survival and disease-free survival of GBM patients. Analysis was performed on prospective (n?=?2) and retrospective (n?=?6) GBM patient tissues, and we finally confirmed that PPAR? expression was distinctly upregulated in MES GBM. Collectively, this study provides insight into PPAR? as a potential therapeutic target for patients with MES GBM.

SUBMITTER: Hua TNM

PROVIDER: S-EPMC7210935 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Peroxisome proliferator-activated receptor gamma as a theragnostic target for mesenchymal-type glioblastoma patients.

Hua Tuyen N M TNM Oh Jiwoong J Kim Sohyun S Antonio Jayson M JM Vo Vu T A VTA Om Jiyeon J Choi Jong-Whan JW Kim Jeong-Yub JY Jung Chan-Woong CW Park Myung-Jin MJ Jeong Yangsik Y

Experimental & molecular medicine 20200413 4

Glioblastomas (GBMs) are characterized by four subtypes, proneural (PN), neural, classical, and mesenchymal (MES) GBMs, and they all have distinct activated signaling pathways. Among the subtypes, PN and MES GBMs show mutually exclusive genetic signatures, and the MES phenotype is, in general, believed to be associated with more aggressive features of GBM: tumor recurrence and drug resistance. Therefore, targeting MES GBMs would improve the overall prognosis of patients with fatal tumors. In thi ...[more]

PMID: 32280134

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Project description:BackgroundDespite the use of combination antiretroviral therapy for the treatment of HIV-1 infection, cognitive impairments remain prevalent due to persistent viral replication and associated brain inflammation. Primary cellular targets of HIV-1 in the brain are macrophages, microglia, and to a certain extent astrocytes which in response to infection release inflammatory markers, viral proteins [i.e., glycoprotein 120 (gp120)] and exhibit impaired glutamate uptake. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily of ligand-activated transcription factors. Compelling evidence suggests that PPAR? exerts anti-inflammatory properties in neurological disorders. The goal of this study was to examine the role of PPAR? in the context of HIV-1ADA gp120-induced inflammation in vitro, in primary cultures of rat astrocytes and microglia, and in vivo, in a rodent model of HIV-1ADA gp120-associated brain inflammation.MethodsPrimary mixed cultures of rat astrocytes and microglia were treated with PPAR? agonists (rosiglitazone or pioglitazone) and exposed to HIV-1ADA gp120. Inflammatory cytokines and indicator of oxidative stress response (TNF?, IL-1?, iNOS) were measured using qPCR, and glutamate transporter (GLT-1) was quantified by immunoblotting. In vivo, rats were administered an intracerebroventricular injection of HIV-1ADA gp120 and an intraperitoneal injection of PPAR? agonist (rosiglitazone) or co-administration with PPAR? antagonist (GW9662). qPCR and immunoblotting analyses were applied to measure inflammatory markers, GLT-1 and PPAR?.ResultsIn primary mixed cultures of rat astrocytes and microglia, HIV-1ADA gp120 exposure resulted in a significant elevation of inflammatory markers and a decrease in GLT-1 expression which were significantly attenuated with rosiglitazone or pioglitazone treatment. Similarly, in vivo, treatment with rosiglitazone reversed the gp120-mediated inflammatory response and downregulation of GLT-1. Furthermore, we demonstrated that the anti-inflammatory effects of PPAR? agonist rosiglitazone were mediated through inhibition of NF-?B.ConclusionOur data demonstrate that gp120 can induce an inflammatory response and decrease expression of GLT-1 in the brain in vitro and in vivo. We have also successfully shown that these effects can be reversed by treatment with PPAR? agonists, rosiglitazone or pioglitazone. Together our data suggest that targeting PPAR? signaling may provide an option for preventing/treating HIV-associated brain inflammation.

Dataset Information

Peroxisome proliferator-activated receptor gamma as a theragnostic target for mesenchymal-type glioblastoma patients.

Publications

Peroxisome proliferator-activated receptor gamma as a theragnostic target for mesenchymal-type glioblastoma patients.

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