Molecular pathways linked to altered fatty acid metabolism in cancer cells

Fatty Acid Synthase (FAS) is the single human enzyme that catalyzes the de novo synthesis of fatty acids in cells. With the exception of liver and adipose tissue, FAS is expressed at low or undetectable levels in most normal adult tissues. However, FAS is over-expressed in many cancers, including lung cancers, and inhibiting FAS has been shown to drive selective apoptosis and decreased growth of cancer cells. Thus, inhibiting FAS is thought to have significant therapeutic potential.;To date, the role of increased FAS activity in cancer, and mechanisms linking inhibition of FAS activity to cancer cell apoptosis are incompletely understood. The current work has investigated molecular pathways linked to altered fatty acid metabolism in cancer cells using a pharmacological FAS inhibitor, C93, as well as inhibitory RNA (RNAi). Results indicate that FAS acts on a wide range of signaling pathways related to apoptosis, metabolism, and cell growth. First, we have shown that inhibiting FAS leads to activation of NF-kappaB, and this activation in turn promotes pro-survival signals, protecting cancer cells (at least in part) to the toxic effects of the FAS inhibition. Previous work has shown that inhibiting FAS results in a rapid decrease in glucose labeling of lung cancer cells, and we have found that decreased glucose transport in lung cancer cells (after treatment with an FAS inhibitor) is linked to decreased expression of the glucose transport protein, Glut4. Additional work described in this thesis provides support for a hypothesis that changes in both NF-kappaB signaling and glucose transport may be triggered by the same effector, Protein Kinase C (PKC). Our studies on PKC show that FAS inhibition drives redistribution of PKC within the cell, and that blocking PKC can both counteract the effects of FAS inhibition on NF-kappaB and stimulate its effects on glucose transport. Finally, the current project has investigated the effects of inhibiting FAS on the Akt apoptotic pathway. Results in these experiments show that FAS inhibition leads to decreased Akt signaling, and also altered signaling of the downstream effectors mTOR and Tuberous Sclerosis Complex 2 (TSC2). Thus, the current study sheds significant light on the mechanisms by which inhibiting fatty acid synthase alters important cellular networks that affect cell survival.