[Androgens and increased lipogenesis in prostate cancer. Cell biologic and clinical perspectives]

Abstract

A search for novel and biologically relevant androgen-regulated genes and processes in the human prostate led to the intriguing observation that androgens provoke a remarkable and coordinated increase in the expression of several genes involved in triglyceride and cholesterol synthesis in various prostatic adenocarcinoma cell lines. This coordinated activation was shown to be the result of a novel and indirect pathway in which androgens cause activation of a secondary transcription regulator, Sterol Regulatory Element Binding Protein (SREBP), a pivotal factor in the control of intracellular lipid homeostasis. The biological relevance of increased lipogenesis in the biology of prostate cancer is underlined by recent immunocytochemical investigations on needle biopsies showing an increase in the expression of Fatty Acid Synthase (FAS) in 94% of the tumor-lesions examined. This increase is already evident in the earliest recognizable lesions (Prostatic Intra-epithelial Neoplasia; PIN) and is more pronounced in tumors with a higher Gleason score, suggesting that increased FAS expression may serve both as an early tumor marker and as a marker of tumor progression. As in tumor cell-lines, increased FAS expression in prostate tumors seems to be only part of a more general and coordinated activation of lipogenic pathways. Further studies revealed that lipogenesis in prostate tumor cells can be enhanced not only by androgens but also by growth factors and by tumor-associated disturbances in signal transduction pathways. EGF, for instance, is also able to activate lipogenesis via the SREBP pathway and activation of the P13 kinase system by inactivation of PTEN (a phenomenon observed in some 50% of the prostate cancers) also causes increased lipogenesis. The early and nearly universal activation of lipogenesis in prostate cancers (and also in various other tumors) suggests that this may be a fundamental event in the development of the tumoral phenotype, an element that certainly merits further investigation. In addition, there are serious indications that interference with enhanced lipogenic activity in tumor cells may cause tumor cell death and delayed tumor development, suggesting that increased lipogenic activity in tumor cells may open a novel avenue for therapeutic intervention.