Effects of Cyclooxygenase-1 or -2 Inhibitors on Expressions of ATP2A2 and ATP2C1 in Cultured Normal Human Keratinocytes

Abstract

Background: Darier's disease (DD) and Hailey-Hailey disease (HHD) are autosomal dominantly inherited skin disorders characterized by the loss of adhesion between epidermal cells and by abnormal keratinization. DD is caused by mutations in ATP2A2, encoding the sarco/endoplasmic reticulum Ca²⁺ ATPase type 2 isoform (SERCA2), and HHD arises from mutations in ATP2C1, a homologue of Golgi secretory pathway Ca²⁺ ATPase (SPCA1). Clinically and histologically, these diseases have common features. Exposure to UVB irradiation exacerbates the skin lesions of both diseases and expressions of ATP2A2 and ATP2C1 mRNA are suppressed by UVB irradiation in cultured normal human keratinocytes. UVB irradiation also induces Cyclooxygenase -2 (COX-2) mRNA expression. Objectives: To examine the effects of COX-1 and COX-2 on ATP2A2 and ATP2C1 mRNA expression. Methods: We used quantitative reverse transcriptase-polymerase chain reactions to examine the effects of celecoxib (a COX-2 selective inhibitor), SC-560 (COX-1 selective), and apigenin, (which is known to prevent UVB-induced COX-2 expression) on UVB-induced suppression of ATP2A2 and ATP2C1 mRNA in vitro. Results: Celecoxib and apigenin increased and SC-560 decreased the levels of UVB-induced suppression of ATP2A2 and ATP2C1 mRNA. Conclusions: These findings suggest that COX-2 suppresses the expression of ATP2A2 and ATP2C1 mRNA, while COX-1 might play an important role in the gene-regulating mechanism of ATP2A2 and ATP2C1 and is required to maintain the homeostasis of Ca²⁺ in keratinocytes.