RETINOIDS STIMULATE LIPID-SYNTHESIS AND ACCUMULATION IN LNCAP PROSTATIC ADENOCARCINOMA CELLS

In a previous report we demonstrated that androgens markedly stimulate accumulation of lipid droplets in LNCaP cells. The effects were alrea dy evident at low concentrations of androgens optimal for proliferatio n but became much more pronounced at high concentrations optimal for d ifferentiation. In the present report we explored whether other agonis ts acting by nuclear receptors and modulating LNCaP growth and differe ntiation also affect lipid accumulation. The agonists investigated wer e 1 alpha,25-dihydroxycholecalciferol (VD3), all-trans-retinoic acid ( atRA), and triiodothyronine (T-3). Lipid accumulation was evaluated by Oil Red O staining followed by image analysis of Oil Red O-stained ce lls or by extraction and measurement of absorbency. Only marginal effe cts were noted for VD3 and T-3. The atRA, on the contrary, increased l ipid staining 5-12-fold. This effect required high concentrations of r etinoids (10(-6) M) and was accompanied by growth stimulation. Lipid a ccumulation was less pronounced than that observed with maximally effe ctive concentrations of androgens (10(-3) M R1881). Thin layer chromat ography (TLC) and enzymatic determination of the various lipid fractio ns demonstrated that retinoids increase triacylglycerides and an unide ntified lipid fraction with a slightly higher mobility. In contrast wi th androgens, however, they did not stimulate the accumulation of chol esterol esters. Incorporation studies with [2-C-14]acetate revealed th at the increased accumulation of the mentioned lipids is related both to increased synthesis and to decreased secretion. Retinoid-induced li pid accumulation is accompanied by increased steady-state levels of th e mRNA encoding fatty acid synthase (FAS), a key enzyme involved in li pid synthesis, while the expression of HMG-CoA-reductase, an enzyme co ntrolling cholesterol synthesis is only marginally affected. It is con cluded that retinoids share the ability of androgens to increase lipid accumulation in LNCaP cells. The nature of the lipids affected by bot h agonists, however, differs at least in part suggesting that the unde rlying mechanisms may also be different. For the studied compounds (an drogens, VD3, atRA, and T-3) no simple and consistent relationship cou ld be observed between their ability to decrease proliferation and inc rease differentiation on the one hand and their ability to promote lip id accumulation on the other hand. (C) 1997 Elsevier Science Ireland L td.