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Aldo-keto reductase 1C3 ( AKR1C3) is an enzyme involved in metabolizing prostaglandins ( PGs) and sex hormones. It metabolizes PGD2 to 9 α11 β- PGF2, diverting the spontaneous conversion of PGD2 to the PPAR γ agonist, 15-Deoxy-Delta-12, 14-prostaglandin J2 (15d- PGJ2). AKR1C3 is overexpressed in various malignancies, suggesting a tumor promoting function. This work investigates AKR1C3 expression in human non-melanoma skin cancers, revealing overexpression in squamous cell carcinoma ( SCC). Effects of AKR1C3 overexpression were then evaluated using three SCC cell lines. AKR1C3 was detected in all SCC cell lines and its expression was upregulated in response to its substrate, PGD2. Although attenuating AKR1C3 expression in SCC cells by si RNA did not affect growth, treatment with PGD2 and its dehydration metabolite, 15d- PGJ2, decreased SCC proliferation in a PPAR γ-dependent manner. In addition, treatment with the PPAR γ agonist pioglitazone profoundly inhibited SCC proliferation. Finally, we generated an SCC cell line that stably overexpressed AKR1C3 ( SCC- AKR1C3). SCC- AKR1C3 metabolized PGD2 to 9 α11 β- PGF2 12-fold faster than the parent cell line and was protected from the antiproliferative effect mediated by PGD2. This work suggests that PGD2 and its metabolite 15d- PGJ2 attenuate SCC proliferation in a PPAR γ-dependent manner, therefore activation of PPAR γ by agonists such as pioglitazone may benefit those at high risk of SCC. [ABSTRACT FROM AUTHOR]

Primary human keratinocytes (PHKs) are known to express the EP3 subtype of prostaglandin E2 receptor. To better understand the role of EP3 receptors in regulating epidermal function, we characterized their expression, localization, and signaling effects in human skin. Three different splice variants of the EP3 receptor (EP3A1, EP3C, and EP3D) were found to be expressed. Immunohistochemical analysis of human skin demonstrated that EP3 receptors were most prominently expressed in the basal and lower spinous layers of the epidermis. The EP3 receptor agonist sulprostone was then used to examine EP3 receptor-dependent keratinocyte signaling pathways and functional effects. We observed that sulprostone inhibits keratinocyte growth at doses between 0.02 and 2 nM and induces sn-1,2-diacylglycerol (DAG) and ceramide production. Concurrent expression of the cell-cycle inhibitory protein p21WAF1 also occurred. These data suggest that EP3 receptors produce epidermal growth inhibition through the action of DAG and ceramide second messengers. [ABSTRACT FROM AUTHOR]