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  • Original Paper
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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 offers 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 effects 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 effects 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 up-regulation of lipogenic gene expression in a subset of cancer cells.

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Acknowledgements

We thank Dr D Templeton for providing us with the plasmid encoding dominant negative MEK. The technical assistance of B Maes is kindly acknowledged. This research was supported by a grant ‘Geconcerteerde Onderzoeksactie van de Vlaamse Gemeenschap’, by research grants from the Fund for Scientific Researh-Flanders (Belgium) (FWO) (to JV Swinnen and to G Verhoeven), by a Cancer Research Grant from FB Insurance, by a grant from the ‘Belgische Federatie tegen Kanker’, by a specialization grant from the Flemmisch Institute for the Enhancement of Scientific-technological Research in the Industry (IWT) to (H Heemers) and by a grant Interuniversity Poles of Attraction Programme-Belgian State, Prime Minister's Office, Federal Office for Scientific, Technical and Cultural Affairs. J Swinnen is a Research Associate of the Fund for Scientific Research-Flanders (Belgium) (FWO).

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Swinnen, J., Heemers, H., Deboel, L. et al. Stimulation of tumor-associated fatty acid synthase expression by growth factor activation of the sterol regulatory element-binding protein pathway. Oncogene 19, 5173–5181 (2000). https://doi.org/10.1038/sj.onc.1203889

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