Epidermal COX-2 Induction Following Ultraviolet Irradiation: Suggested Mechanism for the Role of COX-2 Inhibition in Photoprotection

Abstract

The cyclooxygenase isoforms, COX-1 and COX-2, are involved in the biosynthesis of prostaglandin E2, a major prostaglandin involved in epidermal homeostasis and repair. Cancer originating in the epidermis can develop when keratinocyte proliferation and apoptosis become dysregulated, resulting in sustained epidermal hyperplasia. COX-2 inhibitors, which demonstrate significant in vivo selectivity relative to COX-1, suppress both ultraviolet-induced epidermal tumor development and progression, suggesting that prostaglandin regulation of keratinocyte biology is involved in the pathogenesis of epidermal neoplasia. In this study, we characterized the expression of COX-1 and COX-2, as well as keratinocyte proliferation, differentiation, and apoptosis, following acute ultraviolet irradiation in the hairless SKH-1 mouse. Following acute ultraviolet exposure, COX-2 expression was predominantly induced in the basal keratinocyte layer coincident with an increase in keratinocyte proliferation and apoptosis. The role of COX-2 was further evaluated using a selective COX-2 inhibitor, SC-791, as well as the traditional nonsteroidal COX inhibitor, indomethacin. Following acute ultraviolet irradiation, inhibition of COX-2 with either inhibitor decreased epidermal keratinocyte proliferation. Likewise, keratinocyte apoptosis was increased with COX-2 inhibition, particularly in the proliferating basal keratinocyte layer. There was also a modest inhibition of keratinocyte differentiation. These data suggest that COX-2 expression is probably necessary for keratinocyte survival and proliferation occurring after acute ultraviolet irradiation. We hypothesize that selective COX-2 inhibition, as described herein, may lead to enhanced removal of ultraviolet-damaged keratinocytes, thereby decreasing malignant transformation in the epidermis.

Erbb2 Regulates Inflammation and Proliferation in the Skin after Ultraviolet Irradiation

“…The role of Erbb2 in promoting cell survival may also occur through increased antiapoptotic gene expression, such as Ghr 57 and Ptgs2, which has been shown to promote survival by decreasing apoptosis after UV exposure to keratinocytes. 58 Consistent with these data, cell culture experiments to validate the microarray analysis demonstrated that inhibition or knockdown of Erbb2 increased apoptosis slightly but significantly after UV, implying Erbb2 enhances cell survival after UV. However, the biological significance of an effect of this magnitude remains unclear.…”

Prostaglandin E2 regulates melanocyte dendrite formation through activation of PKCζ

“…The effects of prostaglandins and the cross talk between prostaglandin receptors and their signaling intermediates are of intense interest because of the diverse effects of prostaglandins on cell growth, differentiation and carcinogenesis [3,38,[41][42][43]. While the effects of PGE 2 on epidermal keratinocytes are reasonably well understood [1,[43][44][45], there has been much less investigation in the effects of PGE 2 on human melanocytes.…”

Cyclooxygenase in the Treatment of Glioma: Its Complex Role in Signal Transduction

“…Both EPA and AA are susceptible to enzymatic and nonenzymatic peroxidation of membrane lipids, thus generating large quantities of reactive cytotoxic products that then could control cell proliferation. 39 Elevated COX-2 expression has been reported in pancreatic cancer, 40,41 esophageal cancer, 42 gastric cancer (in which its expression may be a predictor of survival), 43 skin cancers (including melanoma), [44][45][46][47] prostate cancer, [48][49][50][51][52][53][54][55] bladder cancer, [56][57][58] lung cancer (in which expression may also correlate with prognosis), 59,60 ovarian cancer (which also correlates with poor prognosis), 61 cervical cancer (COX-1 is expressed as well), 62 and B-cell lymphoma. 63 Expression in breast cancer has been reported in 36% to 79%.…”