title: Differential activation of catalase expression and activity by PPAR agonists: implications for astrocyte protection in anti-glioma therapy.
abstract: Glioma survival is dismal, in part, due to an imbalance in antioxidant expression and activity. Peroxisome proliferator-activated receptor (PPAR) agonists have antineoplastic properties which present new redox-dependent targets for glioma anticancer therapies. Herein, we demonstrate that treatment of primary cultures of normal rat astrocytes with PPAR agonists increased the expression of catalase mRNA protein, and enzymatic activity. In contrast, these same agonists had no effect on catalase expression and activity in malignant rat glioma cells. The increase in steady-state catalase mRNA observed in normal rat astrocytes was due, in part, to de novo mRNA synthesis as opposed to increased catalase mRNA stability. Moreover, pioglitazone-mediated induction of catalase activity in normal rat astrocytes was completely blocked by transfection with a PPARγ-dominant negative plasmid. These data suggest that defects in PPAR-mediated signaling and gene expression may represent a block to normal catalase expression and induction in malignant glioma. The ability of PPAR agonists to differentially increase catalase expression and activity in normal astrocytes but not glioma cells suggests that these compounds might represent novel adjuvant therapeutic agents for the treatment of gliomas.
authors.affiliation: Department of Radiation Oncology, Free Radical and Radiation Biology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA ; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Nicholas K H
authors.initials: NK
authors.lastname: Khoo
authors.forename: Sachin
authors.initials: S
authors.lastname: Hebbar
authors.forename: Weiling
authors.initials: W
authors.lastname: Zhao
authors.forename: Steven A
authors.initials: SA
authors.lastname: Moore
authors.forename: Frederick E
authors.initials: FE
authors.lastname: Domann
authors.forename: Mike E
authors.initials: ME
authors.lastname: Robbins
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019556:COS Cells; D002374:Catalase / Q000235:genetics* / Q000378:metabolism*; D002522:Chlorocebus aethiops; D005786:Gene Expression Regulation / Q000187:drug effects; D005910:Glioma / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists*; D000077205:Pioglitazone; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D047492:Peroxisome Proliferator-Activated Receptors; D012333:RNA, Messenger; D045162:Thiazolidinediones; D002374:Catalase; D000077205:Pioglitazone
keywords: 9cRA, 9 cis retinoic acid; ActD, actinomycin D; BCNU, 1,3-bis (2-chloroethyl)-1-nitrosourea; C6 glioma cells; CNS, central nervous system; Catalase; DCF, dichlorofluorescein; GPx, glutathione peroxidase; GSH, glutathione; PPAR agonists; PPAR, Peroxisome proliferator-activated receptor; PPARγ-d.n, PPARγ-dominant negative; PPARγ-dominant negative; PPRE, PPAR-response elements; PUFAs, polyunsaturated fatty acids; Pio, Pioglitazone; Primary rat astrocytes; ROS, reactive oxygen species; RXR, retinoid X receptor; Rosi, Rosiglitazone; SOD, superoxide dismutase; TZDs, thiazolidinediones; Transfection; shRNA, short hairpin RNA
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