Investigator: JD Swanson

Scientific Theme: Cancer

Abstract: Gastric cancer is a major health burden throughout the world, and most cases still present late, beyond the possibility of a surgical cure. Unfortunately gastric cancer is relatively resistant to conventional chemotherapeutic agents leading to a 5 year survival of less than 30%. However, plant secondary metabolites provide many leads for new therapeutics that are currently on the market. Unfortunately, their mechanism of action is often not well understood in either plants or animals.  Our preliminary data show that gallic acid, a plant phenolic, seems to have first a proliferative effect, then an antiproliferative effect in the human AGS gastric cancer cell line, in a dosage dependent manner, by potentially mimicking small molecule ligands. While there are some potential pathways reported in the literature across a wide variety of cells, there seems to be no established mechanisms reported by which this compound is working in AGS cells. Therefore we hypothesize that this change in proliferation is due to a gallic acid dosage dependent change in gene expression in pathways involved with controlling the cell cycle.  Furthermore, it is unknown if data collected from the immortalized cancer cell lines relate to what is seen in normal and neoplastic epithelial cells from patient samples.  To test this hypothesis, we will integrate information obtained through a combination of -omic approaches with functional biology.  Two specific aims are to: 1) Compare the functional genetic responses of AGS cells, primary cultures from freshly obtained gastric cancers and normal gastric epithelial cells from patient samples to different gallic acid and the gallic acid derrivative EGCG dosages. 2) Compare transcriptomes from these three cell sources to identify if there are different responses to a range of concentrations of gallic acid/EGCG depending on tissue source. The results from this study will define the physiological role of gallic acidand EGCG as a potential therapeutic for stomach cancer, and may provide mechanisms of action for the therapeutic effects of phenolics in general.  In the future it is expected that these studies will provide a strategy by which assays can be devised to rationally screen for other therapeutically-active natural products.

Human Health Relevance: Many new therapeutics have been identified from natural plant products without knowledge of their therapeutic mechanism in mammalian cells. By defining how these secondary compounds control cell growth in freshly collected stomach cancer cells, normal stomach cells and immortalized cell lines we may provide a more rational approach for the screening of natural products for drug discovery as well as potentially providing a new treatment for gastic cancer. This project has a strong student training.