Inhibition of Fas-apoptosis in Gastric Cancer

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The ability to evade apoptosis or programmed cell death is one of six traits found in all human cancers. Apoptosis resistance allows cells to bypass usual checkpoints that monitor oncogene expression or genomic instability, facilitating the accumulation of genetic mutations and promoting resistance to radio- and chemo- therapy. Mechanism of apoptosis resistance in gastric cancer are poorly studied. Work carried out during the time of my training/transition grant CA90518 defined a critical role for Fas signaling in our well established Helicobacter infection/gastric cancer mouse model. We defined a role for Fas mediated apoptosis in cell loss and atrophy, and defined an acquired resistance as metaplasia and dysplasia progressed to gastric adenocarcinoma. Helicobacter infection in experimentally induced Fas deficiency rapidly leads to invasive gastric adenocarcinoma substantiating a role for acquired resistance in cancer initiaiton and progression. This finding lead us to investigate the mechanisms through which gastric mucosal cells acquire Fas resistance. We have identified 3 distinct levels of acquired Fas resistance in the gastric mucosa which inhibit apoptosis and confer chemoresistance. The central hypothesis of this proposal is resistance to Fas mediated apoptosis contributes to gastric adenocarcinoma formation. In the first specific aim, we will use a combination of in vitro and in vivo approaches to define the requirement of surface receptor abundance in determining mitochondrial dependant and mitochondrial independent Fas apoptotic signaling, define the interaction between MHCII molecules and the Fas pathway, with an emphasis on integrity of lipid raft structures and initiation of PKC and P13-K signaling. In the second specific aim, we will investigate the cellular factors determining FLICE/FLICE vs FLIP/FLICE dimmer formation, the recruitment of adaptor proteins at the DISC which activate Erk1/2 and NF-KB and analyze p38 inhibitiion of signaling. In our third specific aim, we will investigate the abrogation and/or restoration of Fas-apoptotic signaling in a panel of gastric cancer cell lines and test the vivo significance of restoring the Fas apoptotic pathway on tumor growth and response to chemotherapy. The studies outlined in this proposal will determine the signaling mechanisms involved in acquired Fas resistance in gastric mucosal cells. These studies will provide critical insight into novel preventive, and anti-cancer strategies aimed at restoring Fas sensitivity within tumor cells and provide a new direction for cancer treatment.