Fatty Acid Synthase
The primary research focus of the Kridel laboratory is to understand the role of fatty acid synthesis in tumors. Specifically, we are interested in how fatty acid synthase (FAS), the enzyme that catalyzes the terminal steps of fatty acid synthesis, contributes to tumor progression and the anti-tumor mechanisms of FAS inhibitors, especially in prostate cancer.
FAS is expressed at high levels in tumors and expression levels correlate with disease progression and recurrence. The enzyme is unique in that it encodes seven functional domains that work in concert to generate fatty acid.
We were the first to identify Orlistat as an inhibitor of the thioesterase domain of FAS. Inhibition of FAS induces cell death in a range of tumor cell lines and inhibits the growth of prostate tumor xenografts in mice. Our recent work has focused on understanding the mechanism of action of orlistat and other FAS inhibitors. Work by our group has demonstrated that FAS is required for proper function of the endoplasmic reticulum (ER) in tumor cells and that FAS inhibitors induce ER stress in tumor cells.
Current studies are aimed at understanding how the ER stress response may regulate the cell death response when FAS is inhibited. We believe these data provide a teleological link between FAS expression and tumors. In addition, we are also interested in understanding the role of acetyl-CoA carboxylase (ACC) in cancer. ACC catalyzes the rate limiting step in fatty acid biosynthesis. We have made the novel observation that ACC is required for the formation of podosomes and we are interested in understanding the mechanism for this.
Structural Biology
We are also interested in understanding how Orlistat inhibits FAS and using such information to possibly develop new and more effective FAS inhibitors. In collaboration with the Lowther laboratory in the Department of Biochemistry, we have solved the structure of the thioesterase domain of FAS bound by orlistat. This crystal structure represents the first structure of any domain of human FAS bound to a ligand.
The resulting data not only provides a blueprint for the development of novel inhibitors, they may also provide a primer to understand how the thioesterase domain recognizes and cleaves growing fatty acyl chains from the FAS polypeptide. Orlistat may act as a substrate mimetic of palmitoyl-CoA or –ACP and may occupy the same cavity as the natural substrate. In addition, we have an ongoing drug-discovery project aimed at identifying and optimizing novel FAS inhibitors for therapeutic development.
NAD Biosynthesis and Prostate Cancer
There is growing evidence to suggest that NAD is important in cancer. There are multiple mechanisms by which cell obtain or synthesize NAD and multiple pathways that utilize NAD, either as a cofactor or as a substrate.
We are interested in understanding the role of NAD in prostate cancer cells and defining the mechanisms by which prostate cancer cells obtain NAD. Specifically, we are interested in how Nampt regulates tumor cell survival and metabolism.
In addition, we are interested in determining an “NAD fingerprint” in tumor cells through metabolic, lipidomic and genomic profiles.