Androgens stimulate lipogenic gene expression in prostate cancer cells by activation of the sterol regulatory element-binding protein cleavage activating protein/sterol regulatory element-binding protein pathway.
Using two independent prostate cancer cell lines (LNCaP and MDA-PCa-2a), we demonstrate that coordinated stimulation of lipogenic gene expression by androgens is a common phenomenon in androgen-responsive prostate tumor lines and involves activation of the sterol regulatory element-binding protein (SREBP) pathway. We show 1) that in both cell lines, androgens stimulate the expression of fatty acid synthase and hydroxymethylglutaryl-coenzyme A synthase, two key lipogenic genes representative for the fatty acid and the cholesterol synthesis pathway, respectively; 2) that treatment with androgens results in increased nuclear levels of active SREBP; 3) that the effects of androgens on promoter-reporter constructs derived from both lipogenic genes (fatty acid synthase and hydroxymethylglutaryl-coenzyme A synthase) depend on the presence of intact SREBP-binding sites; and 4) that cotransfection with dominant-negative forms of SREBPs abolishes the effects of androgens. Related to the mechanism underlying androgen activation of the SREBP pathway, we show that in addition to minor effects on SREBP precursor levels, androgens induce a major increase in the expression of sterol regulatory element-binding protein cleavage-activating protein (SCAP), an escort protein that transports SREBPs from their site of synthesis in the endoplasmic reticulum to their site of proteolytical activation in the Golgi. Both time course studies and overexpression experiments showing that increasing levels of SCAP enhance the production of mature SREBP and stimulate lipogenic gene expression support the contention that SCAP plays a pivotal role in the lipogenic effects of androgens in tumor cells.
Heemers
H
H
Laboratory for Experimental Medicine and Endocrinology, Faculty of Medicine, Onderwijs en Navorsing, Gasthuisberg, K.U. Leuven, B-3000 Leuven, Belgium.
Maes
B
B
Foufelle
F
F
Heyns
W
W
Verhoeven
G
G
Swinnen
J V
JV
D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D022762:CCAAT-Enhancer-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D019556:COS Cells; D002467:Cell Nucleus / Q000378:metabolism; D002784:Cholesterol / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D064429:Fatty Acid Synthases / Q000235:genetics; D005227:Fatty Acids / Q000096:biosynthesis; D015870:Gene Expression / Q000187:drug effects*; D017930:Genes, Reporter; D006801:Humans; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D007700:Kinetics; D008055:Lipids / Q000096:biosynthesis*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology; D016296:Mutagenesis; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1; D013329:Structure-Activity Relationship; D014157:Transcription Factors; D014162:Transfection; D014407:Tumor Cells, Cultured
D000728:Androgens; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D005227:Fatty Acids; D047908:Intracellular Signaling Peptides and Proteins; D008055:Lipids; D008565:Membrane Proteins; C497387:SREBF1 protein, human; C102196:SREBP cleavage-activating protein; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D002784:Cholesterol; D064429:Fatty Acid Synthases; D006904:Hydroxymethylglutaryl-CoA Synthase