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Ghrelin and des-acyl ghrelin inhibit aromatase expression and activity in human adipose stromal cells: suppression of cAMP as a possible mechanism.

Breast cancer research and treatment (2014-07-25)
Maria M Docanto, Fangyuan Yang, Brid Callaghan, CheukMan C Au, Rahini Ragavan, Xuyi Wang, John B Furness, Zane B Andrews, Kristy A Brown

Aromatase converts androgens into estrogens and its expression within adipose stromal cells (ASCs) is believed to be the major driver of estrogen-dependent cancers in older women. Ghrelin is a gut-hormone that is involved in the regulation of appetite and known to bind to and activate the cognate ghrelin receptor, GHSR1a. The unacylated form of ghrelin, des-acyl ghrelin, binds weakly to GHSR1a but has been shown to play an important role in regulating a number of physiological processes. The aim of this study was to determine the effect of ghrelin and des-acyl ghrelin on aromatase in primary human ASCs. Primary human ASCs were isolated from adipose tissue of women undergoing cosmetic surgery. Real-time PCR and tritiated water-release assays were performed to examine the effect of treatment on aromatase transcript expression and aromatase activity, respectively. Treatments included ghrelin, des-acyl ghrelin, obestatin, and capromorelin (GHSR1a agonist). GHSR1a protein expression was assessed by Western blot and effects of treatment on Ca(2+) and cAMP second messenger systems were examined using the Flexstation assay and the Lance Ultra cAMP kit, respectively. Results demonstrate that pM concentrations of ghrelin and des-acyl ghrelin inhibit aromatase transcript expression and activity in ASCs under basal conditions and in PGE2-stimulated cells. Moreover, the effects of ghrelin and des-acyl ghrelin are mediated via effects on aromatase promoter PII-specific transcripts. Neither the GHSR1a-specific agonist capromorelin nor obestatin had any effect on aromatase transcript expression or activity. Moreover, GHSR1a protein was undetectable by Western blot and neither ghrelin nor capromorelin elicited a calcium response in ASCs. Finally, ghrelin caused a significant decrease in basal and forskolin-stimulated cAMP in ASC. These findings suggest that ghrelin acts at alternate receptors in ASCs by decreasing intracellular cAMP levels. Ghrelin mimetics may be useful in the treatment of estrogen-dependent breast cancer.

Product Number
Product Description

Forskolin, from Coleus forskohlii, ≥98% (HPLC), powder
Forskolin, For use in molecular biology applications
Prostaglandin E2, synthetic, powder, BioReagent, suitable for cell culture
Adenosine 3′,5′-cyclic monophosphate, ≥98.5% (HPLC), powder
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Prostaglandin E2, γ-irradiated, powder, BioXtra, suitable for cell culture
Fura 2-AM, ≥95% (HPLC)
Forskolin, analytical standard
Fura 2-AM, BioReagent, suitable for fluorescence, ≥95.0% (HPLC)
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Dinoprostone, European Pharmacopoeia (EP) Reference Standard
Anti-Tubulin Antibody, beta, clone KMX-1, clone KMX-1, Chemicon®, from mouse