The growth of malignant keratinocytes depends on signaling through the PGE2 receptor EP1

Recent discoveries shed light on the importance of prostaglandin (PG) production in the development of skin cancer. Work by Fischer et al. demonstrates that skin tumor promotion caused by ultraviolet B radiation can be decreased by up to 89% by blocking cyclooxygenase-2 (COX-2) with the drug Celecoxib. A similar study showed that Celecoxib can decrease new tumor formation by 44% in mice that already have tumors. These studies demonstrate the importance of COX-2 and PGs in the development of squamous cell carcinoma. We have explored growth signaling in a model of skin tumor progression. Because changes in PG production have been implicated in skin carcinogenesis, we examined this pathway. We found that malignant cell lines secrete more prostaglandin E-2 (PGE(2)) than the parental cells. We observed increased expression of COX-1 and -2. We also found that these cells express the PGE2 receptors EP1 and EP4. When the cells are grown in the presence of indomethacin, the growth rate of the malignant cells is decreased. This effect can be reversed by addition of PGE2 or an EP1 agonist to the medium. Thus, we have shown that skin tumor cells depend in part on PGE2 signaling through the EP1 prostanoid receptor for their in vitro growth.