RAGE activation by S100P in colon cancer stimulates growth, migration, and cell signaling pathways

PURPOSE: Colon cancer is the third most prevalent cancer in the United States. However, the molecular mechanisms involved in the development and progression of colon cancer are incompletely understood. This study was initiated to explore the potential role of the receptor for advanced glycation end- products and S100P in modulation of key properties of human colon cancer cells. METHODS: Western blot, reverse transcription- polymerase chain reaction, and quantitative polymerase chain reaction were performed for detection of the receptor for advanced glycation end-products and S100P in colon cancer and matched normal colon. The influence of exogenously added S100P was analyzed on SW480 colon cancer cell line proliferation, migration, phosphorylation of mitogen activated protein kinases, and NFkB activation. To identify the mechanisms involved in these responses, coimmuno-precipitation examining the S100P/ Receptor for advanced glycation end- products interaction and the effects of receptor for advanced glycation end- products inhibition in this interaction were analyzed. RESULTS: Although the receptor for advanced glycation end- products was present in normal and malignant colon specimens, only themalignant specimens expressed S100P. Treatment of SW480 cells with S100P increased proliferation and cell migration. Addition of exogenous S100P stimulated both ERK1/ 2 phosphorylation and NFkB activity. The interaction between S100P and the receptor for advanced glycation end- products was demonstrated by coimmunoprecipitation of these molecules from SW480 cells. Antagonism of the receptor for advanced glycation end- products blocked this interaction and the biologic effects of S100P on these cells. CONCLUSIONS: These data indicate that S100P is expressed at greater levels in colon cancer than matched normal tissue and that S100P stimulates colon cancer cell growth, migration, Erk phosphorylation, and NFkB activation in vitro, suggesting that this ligand/ receptor pair may be targeted for the development of new therapies.