Introduction

Since the development of endocrine therapy for the treatment of PCA (1), androgens (As) have been known to play a major regulatory role in PCA cell biology. In a search for novel A-regulated genes, using the LNCaP PCA cell line as an experimental paradigm, As were shown to coordinately stimulate the expression of several genes involved in the synthesis, transport and metabolism of fatty acids and cholesterol (2). Interestingly, increased lipogenesis, characterized by overexpression of fatty acid synthase (FAS), a key enzyme in the biosynthesis of fatty acids, has been observed in many human cancers, including PCA (3). Increased expression of FAS is considered as one of the most common molecular alterations found in PCA (4). As interference with lipogenesis delays tumor growth in several experimental models, these findings may have a significant therapeutic potential (3). In view of these observations, efforts were directed towards identifying the mechanism underlying the lipogenic effects of As in LNCaP PCA cells. These studies revealed that As activate SREBPs (2).

SREBPs are a family oftranscription factors involved in the maintenance of intracellular cholesterol homeostasis, the control of fatty acid synthesis and the differentiation of adipocytes. Synthesized as inactive 125-kDa precursor proteins, SREBPs are anchored into intracellular membranes where they form a complex with SREBP-cleavage activating protein (SCAP). SCAP in turn interacts with a retention protein complex. When cellular sterol levels are low, interaction between SCAP and its retention protein complex is lost, permitting the SREBP/SCAP complex to translocate to the Golgi apparatus. Within this cell organelle two proteases [site 1 protease (S1P) and site 2 protease (S2P)] act to release a 68-kDa aminoterminal SREBP fragment. This transcriptionally active SREBP fragment (nuclear SREBP, nSREBP) migrates to the nucleus, where it activates the transcription of a large set of sterol regulatory element (SRE)-containing genes belonging to the pathways of fatty acid and cholesterol synthesis (5-7) (Figure 1).

Figure 1. Structure and sterol-mediated activation mechanism of SREBPs.

Treatment of LNCaP cells was shown to lead to increased nuclear levels of mature active SREBPs. Moreover, the stimulatory effects ofAs on the expression of key lipogenic genes such as FAS and HMG-CoA-synthase (SYN) depended on

PftOTEiM-TtTC CLEAVAGE

PftOTEiM-TtTC CLEAVAGE

Figure 1. Structure and sterol-mediated activation mechanism of SREBPs.

the presence of intact SREs in the promoter regions of these genes and were counteracted by dominant-negative SREBP forms (2,8). Recently, similar effects of As on SREBP-dependent transcription of lipogenic genes have been described also in MDA-PCa-2a (9) and PC346c (10) PCA cells (8). Taken together, these data provide evidence for the involvement of the SREBP pathway in the A-induction of the lipogenic program in PCA cells. The exact molecular mechanism(s) by which As affect the SREBP pathway remained to be investigated.

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