title: Genetic deficiency or pharmacological inhibition of cyclooxygenase-1 or -2 induces mouse keratinocyte differentiation in vitro and in vivo.
abstract: Previously we demonstrated that genetic deficiency of the cyclooxygenases (COX-1 or COX-2) altered keratinocyte differentiation in mouse skin [Tiano et. al. (2002) Cancer Res. 62, 3395-3401]. In this study, we show that topical application of SC-560 (a COX-1 selective inhibitor) or celecoxib (COX-2 selective) to TPA-treated wild-type skin caused fivefold increases in the number of basal keratinocytes expressing the early differentiation marker keratin 1 (K1). In contrast to skin, COX-2 not COX-1 was the major isoform expressed in cultured primary keratinocytes. COX-1 was predominantly expressed in detached, differentiated cells, whereas COX-2 was found in the attached, proliferating cells. High Ca++ medium induced K1 and COX-1 in wild-type keratinocytes but did not change COX-2 expression. As observed in skin, COX-1-/- and COX-2-/- primary keratinocytes expressed fivefold more K1 than wild-type cells. K1 levels in cultured wild-type keratinocytes were also increased by treatment with celecoxib and indomethacin. However, unlike its in vivo effect, SC-560, possibly due to low COX-1 expression in cultured mouse keratinocytes, did not increase K1 levels. Furthermore, no increases in apoptotic cell numbers were observed in COX-deficient keratinocytes or COX-inhibitor treated wild-type cells. Thus, a major effect of COX inhibitors and COX-deficiency is the induction of keratinocyte differentiation.
authors: Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
authors: Jacqueline K
authors: JK
authors: Akunda
authors: Huei-Chen
authors: HC
authors: Lao
authors: Chris A
authors: CA
authors: Lee
authors: Alisha R
authors: AR
authors: Sessoms
authors: Rachel M
authors: RM
authors: Slade
authors: Robert
authors: R
authors: Langenbach
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D000068579:Celecoxib; D002454:Cell Differentiation; D002478:Cells, Cultured; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D000078404:Epidermal Cells; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000235:genetics; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D007633:Keratins / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D011498:Protein Precursors / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D012878:Skin Neoplasms / Q000188:drug therapy; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D011498:Protein Precursors; D011720:Pyrazoles; C115461:SC 560; D013449:Sulfonamides; C032253:involucrin; D007633:Keratins; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; D000068579:Celecoxib