Inhibition of fatty acid synthase expression by 1alpha,25-dihydroxyvitamin D3 in prostate cancer cells.
1alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)) and its derivatives are a potential treatment of human prostate cancer. The antiproliferative action of 1alpha,25(OH)(2)D(3) is mainly exerted through nuclear vitamin D receptor (VDR)-mediated control of target gene transcription. To explore the target genes which are regulated by 1alpha,25(OH)(2)D(3) in human prostate cancer LNCaP cells, cDNA microarray was performed by using a chip that contains 3000 gene probes. The results showed that 24 genes were regulated by 1alpha,25(OH)(2)D(3). Five of them encode proteins which belong to metabolic enzymes and fatty acid biosynthesis. Fatty acid synthase (FAS) was found to be down-regulated by 1alpha,25(OH)(2)D(3), and the regulation was confirmed by real-time quantitative RT-PCR analysis. Inhibition of FAS expression by 1alpha,25(OH)(2)D(3) in LNCaP cells was more than 50% at 6h. Inhibitory effect of 1alpha,25(OH)(2)D(3) on FAS expression was completely blocked in the presence of protein synthesis inhibitor cycloheximide, indicating that the down-regulation of FAS gene expression by 1alpha,25(OH)(2)D(3) was indirect in LNCaP cells. An inhibition of FAS activity by cerulenin resulted in a strong inhibition of LNCaP cell proliferation. The inhibition of FAS expression and cell proliferation by 1alpha,25(OH)(2)D(3) seemed to be androgen-dependent, since antiandrogen, casodex and DCC-treatment of serum blocked the vitamin D action. The findings suggest that FAS is involved in the antiproliferative effect of 1alpha,25(OH)(2)D(3) in presence of androgens on prostate cancer LNCaP cells.
Qiao
Shengjun
S
Department of Anatomy, Medical School, 33014 University of Tampere, Tampere, Finland. shengjun.qiao@uta.fi
Pennanen
Pasi
P
Nazarova
Nadja
N
Lou
Yan-Ru
YR
Tuohimaa
Pentti
P
D000726:Androgen Antagonists / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology; D002117:Calcitriol / Q000494:pharmacology*; D002569:Cerulenin / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D005485:Flutamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D009570:Nitriles; D020411:Oligonucleotide Array Sequence Analysis; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014105:Tosyl Compounds; D014407:Tumor Cells, Cultured
D000726:Androgen Antagonists; D000813:Anilides; D004791:Enzyme Inhibitors; D009570:Nitriles; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D014105:Tosyl Compounds; D002569:Cerulenin; C014290:hydroxyflutamide; D005485:Flutamide; D003513:Cycloheximide; C053541:bicalutamide; D064429:Fatty Acid Synthases; D002117:Calcitriol