Androgens markedly stimulate the accumulation of neutral lipids in the human prostatic adenocarcinoma cell line LNCaP.

Abstract

Microscopic evaluation of LNCaP cells stained with the lipophilic dye Oil red O revealed that androgens induce a marked stimulation of lipid droplet accumulation. As determined by quantitative analysis of the Oil red O extracted from the stained cells, stimulatory effects of the synthetic androgen R1881 became apparent at concentrations as low as 10(-11) M. Maximal induction (15-fold) was reached at 10(-8) M. Increases were observed 2 days after hormone addition and were maximal 1 day later. Accumulation of lipid droplets was also induced by mibolerone (another synthetic androgen) and by the natural androgens testosterone and dihydrotestosterone. In agreement with the aberrant ligand specificity of the mutated androgen receptor in LNCaP cells, stimulation of lipid accumulation was also apparent after treatment with progesterone and estradiol. Cortisol and the synthetic glucocorticoid dexamethasone were ineffective. The androgen antagonist Casodex (bicalutamide) abolished the stimulatory effect of R1881, further supporting the involvement of the androgen receptor. In agreement with this conclusion, no changes in lipid accumulation were observed after androgen treatment of the androgen receptor-negative prostate tumor lines PC-3 and DU-145. To investigate the nature of the lipids affected by androgens, lipid extracts were analyzed by TLC, complemented with enzymatic lipid analyses. Androgens were shown to have major effects on the content of triglycerides and cholesterol esters (33- and 7-fold stimulation, respectively), the two main classes of lipids stained by Oil red O. Phospholipid and cholesterol contents were increased by a factor of 2. Incorporation studies with [2-14C]acetate revealed that androgens caused a major stimulation of 2-14C incorporation into triglycerides and cholesterol esters (11- and 13-fold, respectively), suggesting that androgens act at least in part at the level of lipid synthesis. Taken together, these findings indicate that androgens, besides affecting proliferation and protein secretion, also markedly stimulate the production and accumulation of neutral lipids, revealing a novel interesting aspect of androgen regulation of LNCaP cells.

Co-targeting AR and HSP90 suppresses prostate cancer cell growth and prevents resistance mechanisms

“…Finally, lipid metabolism is highly regulated by androgens in prostate cancer cells (Swinnen et al 2004). Bicalutamide inhibits lipid synthesis in LNCaP cells (Swinnen et al 1996), and increased levels of key lipogenic enzymes have been reported in CRPC patients (Rossi et al 2003, Ettinger et al 2004.…”

Androgen control of lipid metabolism in prostate cancer: novel insights and future applications

“…In the normal prostate, this anabolic action is essential to maintain the secretory function of the prostate gland required for optimal male fertility. In the case of tumor cells, we observed in 1996 that exposure of LNCaP prostate cells to natural or synthetic androgens leads to a marked accumulation of lipid droplets in the cytoplasm, largely via increased synthesis of fatty acids and cholesterol (Swinnen et al 1996). Importantly, this lipogenesis was reversed by an AR antagonist and was not observed in AR-negative prostate cancer cells.…”

Androgen‐mediated cholesterol metabolism in LNCaP and PC‐3 cell lines is regulated through two different isoforms of acyl‐coenzyme A: Cholesterol Acyltransferase (ACAT)

“…Hager et al initially investigated the role of cholesterol metabolism in prostate cancer and found that during early stage development, large accumulations of membrane associated lipids developed [4]. Furthermore, Swinnen et al [7] correlated androgen stimulation in prostate cancer cells with the accumulation of neutral lipids (triglyceride and cholesterol esters). Sonn et al [8] discovered that exogenous fat intake has also been correlated with prostate cancer mortality and serum androgen levels.…”

“…Upon synthetic androgen (R1881) stimulation of cells, Heemers et al verified an increase in expression of SCAP and SREBPs within the nucleus [17]. This increase in expression did not occur in androgenunresponsive cells and thus this process is believed to be androgen dependent in nature [7].…”