A mechanistic connection between fatty acid synthase and endoplasmic reticulum homeostasis

Fatty acid synthase (FASN) is the enzyme responsible for catalyzing the ultimate steps of fatty acid synthesis in cells. FASN is expressed at high levels in tumor cells but is mostly absent in corresponding normal cells. Because of the unique expression profile of FASN, there is considerable interest not only in understanding its contribution to tumor cell growth and proliferation, but also in developing inhibitors that target FASN specifically as an anti-tumor modality. Work from our lab and the work contained in this thesis provides evidence that: (1) pharmacological blockade of FASN activity induces endoplasmic reticulum stress and subsequent activation of the unfolded protein response; (2) FASN inhibitors can be combined with the proteasome inhibitor bortezomib to enhance UPR-mediated cell death; and (3) FASN inhibitor cell death cannot be protected by inhibition of caspase cleavage, Bcl-2 overexpression, or phosphorylation of eIF2alpha, but may be mediated through accumulation of reactive oxygen species. This work contributes to the larger understanding of FASN in mediating aspects of proliferation, growth and survival. As a result, a clearer understanding of the role of FASN in tumor cells has been developed.