ANDROGENS AND THE CONTROL OF LIPID-METABOLISM IN HUMAN PROSTATE-CANCER CELLS

Since the development of endocrine therapy for the treatment of prosta te cancer, now more than 50 years ago, androgens have been known to pl ay a major role in the regulation of various aspects of the biology of prostate cancer cells. Recently, using the human prostate cancer cell line LNCaP as an experimental paradigm of androgen-sensitive prostate cancer cells, we demonstrated that, apart from their effects on cell proliferation and protein secretion, androgens also induce a marked ac cumulation of cytoplasmic lipid droplets. The accumulating lipids (tri acylglycerols and cholesteryl esters) are at least in part synthesized de novo, suggesting that androgens modulate the expression and/or act ivity of enzymes involved in lipogenesis. One key lipogenic enzyme tha t we have shown to be affected by androgens is fatty acid synthase (FA S), a complex multifunctional enzyme that plays a central role in the synthesis of fatty acids and that recently has been shown to be overex pressed in a variety of cancers, including prostate cancer. Interestin gly, the influence of androgens on lipogenic enzymes is not restricted to FAS alone. Several other enzymes involved in the same metabolic pa thway of fatty acid synthesis are affected as well, as are several key enzymes leading to the synthesis of cholesterol. These findings are r eminiscent of the coordinate control of lipogenic enzymes by the recen tly characterized sterol regulatory element binding proteins (SREBPs) and suggest that androgens might not (only) act directly on the expres sion of all these genes individually, but rather affect the expression and/or activity of these or other transcription factors involved in t he regulation of lipogenic enzymes. Ongoing studies in our laboratory support this concept and provide evidence for the existence of a novel cascade mechanism of androgen action. In view of the recent interest in the prognostic significance of lipogenic enzymes and their potentia l role as targets for antineoplastic therapy, our findings on the regu lation of lipogenic enzymes by androgens not only provide novel insigh ts into the complex mechanisms by which androgens affect prostate canc er cells, but may also open new avenues for diagnosis and therapy. (C) 1998 Elsevier Science Ltd. All rights reserved.