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We have special interests in the roles of the adenomatous polyposis coli (APC) tumor suppressor gene, which is mutated in most sporadic colonic neoplasia, and the K-ras oncogene, which is mutated in a large fraction of colonic and pancreatic neoplasia. We are working to define the normal functions of specific genes in signaling pathways, influenced by APC, leading to cell birth (mitosis) or cell death (apoptosis), and to understand how these functions are altered by mutations. Recent work from our lab has shown that genes involved in arachidonic and amino acid metabolism are downstream effectors of APC and K-ras. We are studying the regulation of enzymes and proteins involved in these metabolic pathways, which produce polyamines and prostaglandins. The polyamines are ubiquitous polycations, and are essential for optimal growth of cells. Inhibiting polyamine and/or prostaglandin synthesis can block epithelial carcinogenesis in experimental animals. Likewise, genetic or pharmacological suppression of cyclooxygenases-1 or -2 (COX-1, COX-2), which produce prostaglandins from arachidonic acid, suppress especially intestinal carcinogenesis. We have found that polyamines and prostaglandins influence cell behaviors, in part, by modulating specific gene expression. Polyamines affect transcription by modifying DNA-protein complex formation, RNA processing via a specific modification of a protein (eIF-5A) involved in RNA transport and degradation, and translation of at least one protein (antizyme) by a novel translational frameshifting mechanism. Prostaglandins influence specific gene expression via their action as ligands for certain transcription factors (PPARs). Lab members are investigating mechanisms of polyamine- and prostaglandin-dependent expression genes in cell and animal models, using cDNA microarray techniques to study global patterns of gene expression and more conventional methodologies to study changes in single genes. We are using this information to develop novel strategies of GI cancer prevention and treatment. We are currently collaborating with physicians at the Arizona Cancer Center and elsewhere to determine whether these strategies can be effectively employed in selected human populations. One current clinical trial involves the treatment of otherwise healthy individuals with precancerous colon polyps, using inhibitors of polyamine synthesis and non-steroidal
anti-inflammatory drugs (NSAIDs).