Stimulation of tumor-associated fatty acid synthase expression by growth factor activation of the sterol regulatory element-binding protein pathway

Increased expression of fatty acid synthase (FAS) is observed in a clinical ly aggressive subset of various common cancers and interference with FAS of fers promising opportunities for selective chemotherapeutic intervention, T he mechanisms by which FAS expression is (up)-regulated in these tumors rem ain, however, largely unknown. Recently we demonstrated that in LNCaP prost ate cancer cells FAS expression is markedly elevated by androgens via an in direct pathway involving sterol regulatory element-binding proteins (SREBPs ), Here, we also show that growth factors such as EGF are able to stimulate FAS mRNA, protein and activity. Several observations also indicate that th e effects of EGF on FAS expression are ultimately mediated by SREBPs, EGF s timulates SREBP-1c mRNA expression and induces an increase in mature nuclea r SREBP-1. Moreover, in transient transfection studies EGF stimulates the t ranscriptional activity of a 178 bp FAS promoter fragment harboring a compl ex SREBP-binding site. Deletion or mutation of this binding site abolishes these effects and ectopic expression of dominant negative SREBP-1 inhibits FAS expression and induction in intact LNCaP cells, Given the frequent dysr egulation of growth factor signaling in cancer and the key role of SREBP-1 in lipid homeostasis, growth factor-induced activation of the SREBP pathway is proposed as one of the mechanisms responsible for upregulation of lipog enic gene expression in a subset of cancer cells.