Abstract
Aldo-keto reductase 1C3 (AKR1C3) is an enzyme involved in metabolizing prostaglandins (PGs) and sex hormones. It metabolizes PGD2 to 9α11β-PGF2 , diverting the spontaneous conversion of PGD2 to the PPARγ 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 siRNA did not affect growth, treatment with PGD2 and its dehydration metabolite, 15d-PGJ2 , decreased SCC proliferation in a PPARγ-dependent manner. In addition, treatment with the PPARγ agonist pioglitazone profoundly inhibited SCC proliferation. Finally, we generated an SCC cell line that stably overexpressed AKR1C3 (SCC-AKR1C3). SCC-AKR1C3 metabolized PGD2 to 9α11β-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 PPARγ-dependent manner, therefore activation of PPARγ by agonists such as pioglitazone may benefit those at high risk of SCC.