Androgen Activation of the Sterol Regulatory Element-Binding Protein Pathway: Current Insights

Abstract

The cellular effects of androgens are mediated by a cognate receptor, the androgen receptor. Typically, the androgen receptor is viewed to exert its activity by binding to androgen response elements located in or near the promoter region of target genes, thereby directly affecting the expression of these genes. However, increasing evidence indicates that androgens may also indirectly influence the expression of genes that do not contain androgen response elements by modulating the activity of secondary transcription factors, mediating the expression of growth factors acting in a paracrine or autocrine fashion, or by inducing changes in the production of other hormones. These indirect effects of androgens can induce cascade-like actions and may play an important role in more complex processes involving coordinated responses of genes, cells, and organs. Previously, our laboratory has identified and characterized a novel indirect mechanism of androgen action involving proteolytical activation of the key lipogenic transcription factor sterol regulatory element-binding protein (SREBP), resulting in the coordinate up-regulation of entire cellular lipogenic pathways. Interestingly, activation of SREBPs by androgens occurs not only under normal physiological conditions but has also been observed in a growing number of pathologies, and more in particular in the setting of steroid-regulated cancers, where increased lipogenesis has been shown to have remarkable diagnostic and prognostic potential and is considered a prime target for novel therapeutic approaches. This review aims to analyze current insights into the molecular mechanism(s) underlying androgen activation of the SREBP pathway and to ascertain the extent to which this phenomenon can be generalized to androgen-responsive cell systems.

Androgen Receptor Survival Signaling Is Blocked by Anti-β2-microglobulin Monoclonal Antibody via a MAPK/Lipogenic Pathway in Human Prostate Cancer Cells

“…In response to the ␤2M-mediated cell signaling, SREBP-1 regulated AR expression by altering AR gene transcription. Conversely, androgens and AR were also found to mediate SREBP-1 expression reciprocally in androgen-responsive prostate cancer cells (40,41). These data, taken together with previous reports from our laboratory and others that documented the regulatory role of ␤2M on AR expression (10) and also androgens and AR regulation of ␤2M expression (8), support the triad relationship among ␤2M, SREBP-1, and AR.…”

Cross-talk between the Androgen Receptor and the Liver X Receptor

“…All SREBP isoforms are activated when an escort protein, SCAP, facilitates migration to the Golgi apparatus (34). It is known that androgens up-regulate SCAP mRNA expression, thus promoting SREBP activation (35). This is confirmed in Fig.…”

“…LXR differentially influences cholesterol and fatty acid homeostasis; while LXR promotes cholesterol depletion, it promotes fatty acid synthesis by directly up-regulating FASN and SREBP-1c expression. Thus, the AR-LXR antagonism should negatively influence SREBP-1c activity, but the AR also promotes SREBP-1c activation by increasing SCAP mRNA levels (35). We found that androgen treatment increased FASN expression and had little influence on SREBP-1c expression (Fig.…”

Microarray coupled to quantitative RT–PCR analysis of androgen-regulated genes in human LNCaP prostate cancer cells

“…Androgen regulation of steroid-biosynthesis genes is mediated through an indirect mechanism involving the activation of sterol regulatory-element binding proteins SREBP-1 and SREBP-2 (Heemers et al, 2006). Further, kruppel-like factor 5 (KLF5) has recently been identified as an androgen-regulated gene that acts as a positive regulator of SREBP-1 function (Lee et al, 2009).…”