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 already evident at low concentrations of androgens optimal for proliferation but became much more pronounced at high concentrations optimal for differentiation. In the present report we explored whether other agonists acting by nuclear receptors and modulating LNCaP growth and differentiation also affect lipid accumulation. The agonists investigated were 1alpha,25-dihydroxycholecalciferol (VD3), all-trans-retinoic acid (atRA), and triiodothyronine (T3). Lipid accumulation was evaluated by Oil Red O staining followed by image analysis of Oil Red O-stained cells or by extraction and measurement of absorbency. Only marginal effects were noted for VD3 and T3. The atRA, on the contrary, increased lipid staining 5-12-fold. This effect required high concentrations of retinoids (10[-6] M) and was accompanied by growth stimulation. Lipid accumulation was less pronounced than that observed with maximally effective concentrations of androgens (10[-3] M R1881). Thin layer chromatography (TLC) and enzymatic determination of the various lipid fractions demonstrated that retinoids increase triacylglycerides and an unidentified lipid fraction with a slightly higher mobility. In contrast with androgens, however, they did not stimulate the accumulation of cholesterol esters. Incorporation studies with [2-14C]acetate revealed that the increased accumulation of the mentioned lipids is related both to increased synthesis and to decreased secretion. Retinoid-induced lipid accumulation is accompanied by increased steady-state levels of the mRNA encoding fatty acid synthase (FAS), a key enzyme involved in lipid synthesis, while the expression of HMG-CoA-reductase, an enzyme controlling cholesterol synthesis is only marginally affected. It is concluded that retinoids share the ability of androgens to increase lipid accumulation in LNCaP cells. The nature of the lipids affected by both agonists, however, differs at least in part suggesting that the underlying mechanisms may also be different. For the studied compounds (androgens, VD3, atRA, and T3) no simple and consistent relationship could be observed between their ability to decrease proliferation and increase differentiation on the one hand and their ability to promote lipid accumulation on the other hand.
Esquenet
M
M
Laboratory for Experimental Medicine and Endocrinology, Onderwijs en Navorsing, Gasthuisberg, Leuven, Belgium.
Swinnen
J V
JV
Van Veldhoven
P P
PP
Denef
C
C
Heyns
W
W
Verhoeven
G
G
D000085:Acetates / Q000378:metabolism; D000230:Adenocarcinoma / Q000378:metabolism*; D001391:Azo Compounds; D002117:Calcitriol / Q000494:pharmacology*; D004396:Coloring Agents; D064429:Fatty Acid Synthases / Q000235:genetics; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics; D008055:Lipids / Q000096:biosynthesis*; D008297:Male; D015741:Metribolone / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D045165:Testosterone Congeners / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology*; D014284:Triiodothyronine / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000085:Acetates; D001391:Azo Compounds; D004396:Coloring Agents; D008055:Lipids; D012333:RNA, Messenger; D045165:Testosterone Congeners; D014284:Triiodothyronine; D015741:Metribolone; D014212:Tretinoin; D006903:Hydroxymethylglutaryl CoA Reductases; D064429:Fatty Acid Synthases; D002117:Calcitriol; C011049:oil red O