Studies on tumor promotion and progression: The importance of signaling by activator protein-1 and prostaglandin E₂

Abstract

It is clear that non-melanoma skin cancers have a significant impact on the health of the general population. With over one million new cases expected this year the extent of the problem is increasing. Extensive research on the molecular mechanisms of tumor promoting agents has yielded a large body of evidence suggesting that activity of the transcription factor activator protein-1 is central to development of benign lesions. Recently, a dominant negative c jun, TAM-67, has been shown to block tumor promotion by 12-O-tetradecanoylphorbol-13-acetate. In order to determine if this is a more general phenomenon, we examined the effects of TAM-67 on okadaic acid induced tumor promotion. We found that TAM-67 could effectively inhibit tumorigenesis induced by okadaic acid. In order to further characterize the activity of TAM-67, we identified its molecular mechanism of action in suppressing okadaic acid induced activator protein-1 activity. These studies led to identification of squelching as the mechanism of action. This work also revealed that TAM-67 could interact with all the proteins of the Jun and Fos families as well as non-activator protein-1 proteins. Thus, TAM-67 may be able to affect multiple pathways including activator protein-1. Other work has identified prostaglandin signaling as a major factor in the development of non-melanoma skin cancer. We identified production of prostaglandin E2 as one of the abnormalities in a model of skin tumor progression. The cell lines examined were able to make prostaglandin E2, and also expressed receptors for it. We therefore examined the importance of this apparent autocrine loop and found that the cells that produce prostaglandin E2 depend on signaling from the prostaglandin E2 receptor EP1 for a normal in vitro growth rate. Both transactivation by activator protein-1 and signaling by prostaglandins are involved in chemically induced skin carcinogenesis. The magnitude of the problem ensures that demand for new treatments will only increase. Obtaining a clear understanding of the molecular events associated with the growth and transformation of cells from normal to benign to malignant is crucial to identifying novel treatment and prevention strategies.