Prostate cancer has a prevalence of 33% and is the third highest cause of cancer-related death in American males (25). In cancer biology, the primary tumor is usually not the main cause of patient death, but rather metastasis of the tumor cells. During the transition from localized to metastatic cancer, cells undergo changes in adhesion and morphology in a process referred to as the epithelial-mesenchymal transition (EMT) (8). This process results in breakdown of intercellular junctions which results to increased cell migratory potential. Several signaling pathways regulate the cell adhesion molecules that maintain an epithelial architecture. Rap1 is one of the signaling cascades that has been shown to regulate most integrins receptors as well as E-cadherin-mediated cell adhesions (20, 21). Our goal is to elucidate the role of Rap1 in cell migration, invasion and survival and to determine how alteration of its signals might play a role in increased tumor aggressiveness. Studies done by our lab and that of our collaborators have shown that downregulation of the Rap1 signaling pathway may be critical for hypoxia-induced cellular migration. It has long been hypothesized that hypoxia can initiate metastatic processes, but the mechanisms underlying this process are not well defined. HIF-1 alpha is a heterodimeric transcription factor that regulates genes essential for survival in hypoxic environments. We hypothesize that HIF-1 alpha regulates RaplA and that decreased Rap1 signaling is important for prostate cancer metastasis. The goals of this project are to elucidate the mechanism of transcriptional regulation of RAP1 genes and the role of Rap1 signals in tumor metastasis. Furthermore, the proposed research will increase our understanding of fundamental cellular processes relevant to tumor cell adhesion, migration, invasion, and survival. This research will help validate the Rap1 pathway as a possible new target for therapies to treat prostate cancer metastasis.
