Dr. Alice Pentland's research addresses the role of phospholipases and cyclooxygenases in epidermal function. There are two major areas these studies address: their role in carcinogenesis and in cell differentiation. The role of these lipid mediators in the induction of squamous cell carcinoma of the skin is being studied in the context of ultraviolet light injury. Recent work has shown that available cyclooxygenase inhibitors have anti tumor properties in colon cancer in humans. UV exposure results in substantial increases in cyclooxygenase product formation; work in the lab is therefore designed to directly link UV-induced cyclooxygenase product formation to tumor initiation and promotion in humans. The validity of this hypothesis is being tested by showing 1) cyclooxygenase metabolite formation is induced by chronic irradiation and in squamous cell carcinoma, 2) that the increased quantities of these metabolites formed in epidermis produce in vitro changes supportive of tumor formation and 3) that UV carcinogenesis is decreased in knockout animals lacking prostaglandin forming enzymes.

Cyclooxygenase acts coordinately with phospholipases, and so thorough understanding of the mechanisms which regulate PLA2 expression and activity in epidermis must also be defined. Both cytosolic and secretory forms of phsopholipase are under study. These experiments are designed to link induction of PLA2 synthesiswith shape change in the cell (as is found in wound repair) and define the key signaling pathways initiating changes in PLA2 activity.

In vitro and in vivo approaches are used to address these questions. In vitro, the overexpression of cyclooxygenase and phospholipase enzymes on the injury response of cell cultures are currently being examined. The impact of product synthesis on cell cycle progression, differentiation and apoptosis are a central focus. The in vitro work is examined in coordiantion with studies in knockout mice. In addition to this examination of phospholipases and cyclooxygenases in skin, the role of prostaglandin receptor regulation of these functions is also being examined.

Konger R, Malaviya R, Pentland AP: Growth regulation of primary human keratinocytes by prostaglandin E receptor EP2 and EP3 subtypes. Biochimica et Biophysica Acta 1401:221-234, 1998.

Buckman S, Gresham A, Hale P, Hruza G, Anast J, Masferrer J and Pentland AP. COX-2 expression is induced by UVB exposure in human skin: Implications for the development of skin cancer. Carcinogenesis 19:5:723-729, 1998.