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PPAR? agonists target aromatase via both PGE2 and BRCA1.

ABSTRACT: Obesity is a well-recognized risk factor for postmenopausal breast cancer. Although the underlying mechanisms are not clearly defined, aromatase is thought to play a pivotal role in connecting obesity-associated inflammation with postmenopausal breast cancer. It has been well established that both the proinflammatory prostaglandin E(2) (PGE(2)) and the BRCA1 tumor-suppressor gene regulate aromatase expression. In this issue of the journal (beginning on p. 1183), Subbaramaiah and colleagues improve our understanding of the molecular mechanisms by which PPAR? inhibits aromatase expression. They found that pioglitazone, a PPAR? agonist, inhibited aromatase expression by inhibition of PGE(2) signaling and upregulation of BRCA1. Their findings provide potential targets for preventing or treating obesity-related breast cancer.

SUBMITTER: Margalit O

PROVIDER: S-EPMC3466470 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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PPARγ agonists target aromatase via both PGE2 and BRCA1.

Margalit Ofer O Wang Dingzhi D Dubois Raymond N RN

Cancer prevention research (Philadelphia, Pa.) 20121001 10

Obesity is a well-recognized risk factor for postmenopausal breast cancer. Although the underlying mechanisms are not clearly defined, aromatase is thought to play a pivotal role in connecting obesity-associated inflammation with postmenopausal breast cancer. It has been well established that both the proinflammatory prostaglandin E(2) (PGE(2)) and the BRCA1 tumor-suppressor gene regulate aromatase expression. In this issue of the journal (beginning on p. 1183), Subbaramaiah and colleagues impro ...[more]

PMID: 23041473

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Project description:Nicotinic acetylcholine receptors (nAChRs) are involved in seizure mechanisms. Hence, nocturnal frontal lobe epilepsy was the first idiopathic epilepsy linked with specific mutations in ?4 or ?2 nAChR subunit genes. These mutations confer gain of function to nAChRs by increasing sensitivity toward acetylcholine. Consistently, nicotine elicits seizures through nAChRs and mimics the excessive nAChR activation observed in animal models of the disease. Treatments aimed at reducing nicotinic inputs are sought as therapies for epilepsies where these receptors contribute to neuronal excitation and synchronization. Previous studies demonstrated that peroxisome proliferator-activated receptors-? (PPAR?), nuclear receptor transcription factors, suppress nicotine-induced behavioral and electrophysiological effects by modulating nAChRs containing ?2 subunits. On these bases, we tested whether PPAR? agonists were protective against nicotine-induced seizures. To this aim we utilized behavioral and electroencephalographic (EEG) experiments in C57BL/J6 mice and in vitro patch clamp recordings from mice and rats. Convulsive doses of nicotine evoked severe seizures and bursts of spike-waves discharges in ?100% of mice. A single dose of the synthetic PPAR? agonist WY14643 (WY, 80 mg/kg, i.p.) or chronic administration of fenofibrate, clinically available for lipid metabolism disorders, in the diet (0.2%) for 14 days significantly reduced or abolished behavioral and EEG expressions of nicotine-induced seizures. Acute WY effects were reverted by the PPAR? antagonist MK886 (3 mg/kg, i.p.). Since neocortical networks are crucial in the generation of ictal activity and synchrony, we performed patch clamp recordings of spontaneous inhibitory postsynaptic currents (sIPSCs) from frontal cortex layer II/III pyramidal neurons. We found that both acute and chronic treatment with PPAR? agonists abolished nicotine-induced sIPSC increases. PPAR? within the CNS are key regulators of neuronal activity through modulation of nAChRs. These effects might be therapeutically exploited for idiopathic or genetically determined forms of epilepsy where nAChRs play a major role.

Project description:BackgroundIntestinal fibrosis is a serious complication of inflammatory bowel disease, including Crohn's disease and ulcerative colitis. There is no specific treatment for intestinal fibrosis. Studies have indicated that peroxisome proliferator-activated receptor- ? (PPAR-?) agonists have anti-fibrogenic properties in organs besides the gut; however, their effects on human intestinal fibrosis are poorly understood. This study investigated the anti-fibrogenic properties and mechanisms of PPAR-? agonists on human primary intestinal myofibroblasts (HIFs).MethodsHIFs were isolated from normal colonic tissue of patients undergoing resection due to colorectal cancer. HIFs were treated with TGF-?1 and co-incubated with or without one of two synthetic PPAR-? agonists, troglitazone or rosiglitazone. mRNA and protein expression of procollagen1A1, fibronectin, and ?-smooth muscle actin were determined by semiquantitative reverse transcription-polymerase chain reaction and Western blot. LY294002 (Akt inhibitor) was used to examine whether Akt phosphorylation was a downstream mechanism of TGF-?1 induced expression of procollagen1A1, fibronectin, and ?-smooth muscle actin in HIFs. The irreversible PPAR-? antagonist GW9662 was used to investigate whether the effect of PPAR-? agonists was PPAR-? dependent.ResultsBoth PPAR-? agonists reduced the TGF-?1-induced expression of ?-smooth muscle actin which was integrated into stress fibers in HIFs, as determined by actin microfilaments fluorescent staining and ?-smooth muscle actin-specific immunocytochemistry. PPAR-? agonists also inhibited TGF-?1-induced mRNA and protein expressions of procollagen1A1, fibronectin, and ?-smooth muscle actin. TGF-?1 stimulation increased phosphorylation of downstream signaling molecules Smad2, Akt, and ERK. TGF-?1 induced synthesis of procollagen1A1, fibronectin, and ?-smooth muscle actin through a phosphatidylinositol 3-kinase/Akt-dependent mechanism. PPAR-? agonists down regulated fibrogenesis, as shown by inhibition of Akt and Smad2 phosphorylation. This anti-fibrogenic effect was PPAR-? independent.ConclusionsTroglitazone and rosiglitazone suppress TGF-?1-induced synthesis of procollagen1A1, fibronectin, and ?-smooth muscle actin in HIFs and may be useful in treating intestinal fibrosis.

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PPAR? agonists target aromatase via both PGE2 and BRCA1.

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PPARγ agonists target aromatase via both PGE2 and BRCA1.

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