Orlistat is an irreversible inhibitor of FASN activity with cytotoxic properties on several cancer cell lines that inhibits tumor progression and metastasis in prostate cancer xenografts and experimental melanomas, respectively.
Here, we show that the abilities of FASN and MAGL to promote nuclear receptor activation and PCa metastasis are critically dependent upon co-expression of FABP5 in vitro and in vivo.
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.
Of these cases, 92% overexpressed fatty acid synthase (FAS) in cancerous cells and 84.7% exhibited the signature of FAS overexpression and SCD loss in prostate carcinoma as compared to normal prostate epithelium.
The link between prostate cancer (PC) development and lipid metabolism is well established, with AR intimately involved in a number of lipogenic processes involving SREBP1, PPARG, FASN, ACC, ACLY and SCD1.
Similarly, overweight patients with elevated tumor FASN expression had a 2.73 (95% CI, 1.05 to 7.08) times higher risk of lethal PCa (P(interaction) = .02).
To examine mechanisms, we established FASN knockdown prostate cancer cells by transduction of short-hairpin RNA against FASN and investigated the characteristics by analyses on morphology and cell behavior and microarray-based gene expression profiling.
Here, we show positive correlation between PPARγ and FASN protein in PCa cell lines and synergism between TZDs and FASN blockers in PCa cell viability reduction and apoptosis induction.
Whereas the latter group of tumors expressed some proapoptotic genes, tumors with high FAS levels overexpressed, among other genes, its transcriptional regulator, steroid regulator binding protein, and apolipoprotein E. These data demonstrate (1) the consistent overexpression of FAS in prostate carcinoma compared with the adjacent normal tissue, (2) a strong association between FAS and prostate tumor initiation and progression, (3) the highest FAS expression occurring in androgen-independent bone metastases, (4) the transcriptional and posttranscriptional regulation of FAS in the majority and in a subset of prostate cancers, respectively, and (5) most importantly, the identification by FAS expression of prostate tumors with unique molecular signatures and potentially diverse biologic behavior.
These observations suggest that FASN can act as a prostate cancer oncogene in the presence of AR and that FASN exerts its oncogenic effect by inhibiting the intrinsic pathway of apoptosis.
In the present study, we showed that KLF5 acts as a key regulator controlling the expression of FASN (fatty acid synthase) through an interaction with SREBP-1 (sterol-regulatory-element-binding protein-1) in the androgen-dependent LNCaP prostate cancer cell line.
Up-regulation and increased activity of lipogenic enzymes (including fatty acid synthase and choline kinase) occurs throughout PCa carcinogenesis and correlates with worse prognosis and poor survival.
Our previous work has shown up-regulated mRNA of the transcription factor early growth response 1 (EGR-1) and the lipogenic enzyme fatty acid synthase (FAS) in tissues adjacent to prostate cancer.
Here, using an RNA array hybridisation technique complemented by in situ hybridisation, we report that in prostate cancerfatty acid synthase expression is up-regulated at the mRNA level together with other enzymes of the same metabolic pathway.
Immunohistochemistry analysis revealed that expression of P300 protein positively correlates with FASN protein levels in a cohort of human PCa specimens.
Consistent with these observations, the expression of the <i>SREBF1, FASN,</i> and <i>SCD1</i> genes is significantly correlated in human prostate cancer tumor clinical specimens.
These data suggest that CaP patients could be stratified in terms of PPARG/FASN and PTEN levels to identify patients with aggressive CaP who may respond favorably to PPARG/FASN inhibition.
A hallmark of prostate cancer progression is dysregulation of lipid metabolism via overexpression of fatty acid synthase (FASN), a key enzyme in de novo fatty acid synthesis.