Fig. 8.

FASN inhibition blocks metabolic and signal transduction pathways vital to cancer cell growth, proliferation, and survival. FASN inhibition results in inhibition of Akt and S6 phosphorylation in the AKT–mTOR signal transduction pathway. In the Wnt–β-catenin pathway, FASN inhibition results in the inhibition of Lrp6 and β-catenin phosphorylation as well as the expression of TCF promoter-driven genes such as c-Myc. FASN inhibition impairs the plasma membrane localization of palmitoylated and other lipid-raft-associated proteins such as N-Ras. Our data fit a model whereby the disruption of lipid rafts and mislocalization of membrane-associated proteins can drive inhibition of signaling through cellular growth and survival pathways such as AKT–mTOR and Wnt–β-catenin. Signal transduction through molecules such as K-Ras or pathways such as AKT–mTOR is tightly linked with tumor cell metabolism of glucose and glutamine as well as lipid biosynthesis.