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Stimulation of tumor-associated fatty acid synthase expression by growth factor activation of the sterol regulatory
J V Swinnen1, H Heemers, L Deboel
1Laboratory for Experimental Medicine and Endocrinology, Faculty of Medicine, Onderwijs en Navorsing, Gasthuisberg, K.U. Leuven, Herestraat 49, B-3000 Leuven, Belgium.
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.
Insights
Growth factors like EGF stimulate fatty acid synthase (FAS) expression in cancer cells by activating sterol regulatory element-binding proteins (SREBPs). This pathway is crucial for increased lipogenic gene expression in certain aggressive cancers.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Fatty acid synthase (FAS) is upregulated in aggressive cancers, presenting a therapeutic target.
- Mechanisms regulating FAS expression in tumors are largely unknown.
- Androgens indirectly increase FAS in LNCaP prostate cancer cells via sterol regulatory element-binding proteins (SREBPs).
Purpose of the Study:
- To investigate the role of growth factors, specifically EGF, in regulating FAS expression.
- To elucidate the signaling pathway mediating EGF-induced FAS upregulation.
- To determine if SREBPs are involved in growth factor-driven FAS expression.
Main Methods:
- Studied the effects of EGF on FAS mRNA, protein, and activity in LNCaP cells.
- Analyzed SREBP-1c mRNA expression and nuclear SREBP-1 levels.
- Utilized transient transfection assays with FAS promoter fragments and dominant-negative SREBP-1.
- Investigated SREBP-binding sites within the FAS promoter.
Main Results:
- EGF significantly stimulates FAS mRNA, protein, and activity.
- EGF increases SREBP-1c mRNA and mature nuclear SREBP-1 levels.
- EGF enhances the transcriptional activity of the FAS promoter via an SREBP-binding site.
- Mutating or deleting the SREBP-binding site abolishes EGF's effect.
- Dominant-negative SREBP-1 inhibits EGF-induced FAS expression.
Conclusions:
- Growth factors, such as EGF, activate FAS expression through the SREBP pathway.
- Growth factor-induced SREBP activation is a mechanism for lipogenic gene upregulation in some cancer cells.
- This highlights the importance of the SREBP pathway in cancer lipid metabolism and growth.