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.