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.

 

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 acts as a substrate mimetic of palmitoyl-CoA or –ACP and may occupy the same cavity as the natural substrate.

Adipokines/Obesity and Prostate Cancer

There is growing evidence to suggest that obesity impacts There is growing evidence to suggest that obesity impacts negatively on prostate cancer. Among the speculated mechanisms, adipokines have become a primary interest. Adipokines are growth factors that are secreted from adipose tissue. A second interest in the laboratory in understanding how adipokines may affects prostate tumor proliferation, survival and metabolism. Specifically, we are interested in how one adipokine, visfatin, may influence prostate tumor cells. Recent experiments have demonstrated that visfatin can induce proliferation of prostate tumor cells and induce fatty acid synthase expression. We have also demonstrated that visfatin can be expressed and secreted from prostate tumor cells. This leads us to hypothesize that visfatin can act in both an endocrine (from adipose tissue) and a paracrine (from the prostate) manner to affect prostate cancer.

Ongoing Projects

Ongoing project include understanding the anti-tumor effects of FAS inhibitors, structural analysis of FAS inhibitors and substrates, the effects of FAS inhibitors on tumor growth in vivo, and understanding how the fatty acid synthesis pathway regulates global tumor cell metabolism. These projects are funded by grant from the NIH/NCI and the Department of Defense. Project directed at understanding the effects of adipokines and obesity on prostate cancer are also ongoing.