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

Abstract

Increased expression of fatty acid synthase (FAS) is observed in a clinically aggressive subset of various common cancers and interference with FAS oers promising opportunities for selective chemotherapeutic intervention. The mechanisms by which FAS expression is (up)-regulated in these tumors remain, however, largely unknown. Recently we demonstrated that in LNCaP prostate cancer cells FAS expression is markedly elevated by androgens via an indirect 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 the eects of EGF on FAS expression are ultimately mediated by SREBPs. EGF stimulates SREBP-1c mRNA expression and induces an increase in mature nuclear SREBP-1. Moreover, in transient transfection studies EGF stimulates the transcriptional activity of a 178 bp FAS promoter fragment harboring a complex SREBP-binding site. Deletion or mutation of this binding site abolishes these eects and ectopic expression of dominant negative SREBP-1 inhibits FAS expression and induction in intact LNCaP cells. Given the frequent dysregulation 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 lipogenic gene expression in a subset of cancer cells. Oncogene (2000) 19, 5173 ± 5181.

SLC37A1 Gene expression is up-regulated by epidermal growth factor in breast cancer cells

“…Although the ultimate mechanisms responsible for tumor-associated FAS overexpression are not completely understood, growth factor and hormone transduction pathways have been indicated as major contributors. In this regard, FAS expression has been shown to be stimulated by EGF signaling [32], which involves a complex network including activation and/or cross-talk between multiple signal-transduction cascades. For example, MAPK and PI3K pathways are likely candidates for regulating FAS expression in cancer cells through SREBP-1c [33,34].…”

Suppression of fatty acid synthase in MCF-7 breast cancer cells by tea and tea polyphenols: a possible mechanism for their hypolipidemic effects

“…5 Factors that have shown to play an important role in the control of lipogenic enzyme in cancer cells are growth factors such as EGF, of which the signaling pathways are frequently dysregulated and constitutively activated in cancer cells. 22 One of the intracellular signaling pathways that are frequently activated in cancer cells is the PI3K/Akt kinase pathway. 23 This pathway has been documented as an important signaling for cell survival, cell transformation and tumor growth.…”

Effects of olive oil polyphenols on fatty acid synthase gene expression and activity in human colorectal cancer cells

“…A substantial subset of common human cancers, including colon cancer, express elevated levels of fatty acid synthase (FAS), a key anabolic enzyme that catalyzes the terminal steps in the novo biosynthesis of fatty acids [8, 13,20,23,24]. In breast and prostate carcinomas, high levels of FAS expression are associated with poor clinical outcome, suggesting a relationship between FAS expression and tumor aggressiveness [1,24].…”

“…In breast and prostate carcinomas, high levels of FAS expression are associated with poor clinical outcome, suggesting a relationship between FAS expression and tumor aggressiveness [1,24]. FAS expression also appears to play an important role in the growth and pathogenesis of colon carcinoma [20].…”