Emmanuelle Meuillet, PhD, has developed a novel Akt inhibitor which structure is based on its similarity with the substrate for PdtIns-3-Kinase, i.e. phosphatidyl-myo-inositol-phosphate. In collaboration with Dr. E. Mash (University of Arizona, analogues such as the D-3-Deoxy-phosphatidyl-myoinositol (3-DPI) and the D-3-Deoxy-phosphatidyl-myoiinositol ether lipid (3-DPIEL) were synthesized and tested for their ability to bind the pleckstrin homology domain of Akt and thus inhibit the kinase activity in vitro and in vivo.
The discovery of the possible interaction and regulation of the PdtIns-3-Kinase/Akt/PTEN pathway by a small redox protein, thioredoxin is of great relevance in cancer research. Dr. Meuillet’s lab has recently demonstrated a direct interaction between thioredoxin and the tumor suppressor, PTEN. This project is extensively researched in her lab as it represents her primary funding source at this moment (NIH-RO1 funded for 4 years). One way to study the interaction of these proteins on a genetic level was to use small organism systems such as Drosophila. Using such a system, she has shown a genetic and phenotypic interaction between the tumor suppressor PTEN and the redox protein Thioredoxin-1 in collaboration with Dr. Brabant M. (Director of the Small Organism Facility Core, Arizona Cancer Center). Finally, one way to modulate the interaction between PTEN and thioredoxin exists via the regulation of the thioredoxin reductase activity, using seleno-compounds. Thus, Dr. Meuillet is also studying the importance of sodium selenite and selenomethionine in cancer prevention. This funded project is in collaboration with Dr. Mark Nelson (Department of Pathology, NIH-RO1, funded for 5 year, Co-PI). Several seleno-compounds have been shown to possess chemopreventive effects in various types of cancers, such as colon and prostate cancers. Again this project may the use of small organism systems such as Drosophila.
Future research plans include bridging the gap between understanding the role of lipids and exploring signal transduction pathways mainly in diabetes and cancer. Interest exists in investigating how lipids, carbohydrates and kinases interact in normal and abnormal conditions as well as establishing relationships to diets, diseases and prevention. These specific interactions between protein and lipids can be studied at several levels: molecularly by investigating structurally these possible interactions, biochemical by analyzing membrane microdomains in normal and abnormal conditions and finally genetically by exploring gene expression. The investigation of selective inhibition or activation of oncogenes by lipids through the analysis of gene expression-modulation by specific nutrients, or via the molecular study of the occurrence of such interactions may lead to the development of new areas in cancer chemo-prevention, diabetes treatment as well as cancer treatment.