Abstract
Simple SummaryTWEAK is an inflammatory cytokine related to prostate cancer (PCa) progression that exerts its effects by engaging its cognate receptor Fn14. A soluble form of TWEAK (sTWEAK) has been detected in the PCa microenvironment. Altered levels of circulating sTWEAK are associated with aberrant glucose metabolism. We show that reduced serum levels of sTWEAK are associated with the metabolic status in patients with PCa and that the treatment of PC-3 cells with sTWEAK enhances the expression of genes related to lipid, but not to glucose, metabolism. sTWEAK also increases the lipid uptake and lipid accumulation in PC-3 cells. We corroborated that the observed effects were due to TWEAK/Fn14 engagement by silencing Fn14 expression, which attenuated the aberrant gene and protein expression. Additionally, we observed that the phosphorylation of ERK1/2 and AKT (ser473) were required for TWEAK/Fn14 actions. Thus, the contribution of the sTWEAK/Fn14 axis on PCa metabolism supports its potential as a therapeutic target for PCa.Soluble TWEAK (sTWEAK) has been proposed as a prognostic biomarker of prostate cancer (PCa). We found that reduced serum levels of sTWEAK, together with higher levels of prostate-specific antigen and a higher HOMA-IR index, are independent predictors of PCa. We also showed that sTWEAK stimulus failed to alter the expression of glucose transporter genes (SLC2A4 and SLC2A1), but significantly reduced the expression of glucose metabolism-related genes (PFK, HK1 and PDK4) in PCa cells. The sTWEAK stimulation of PC-3 cells significantly increased the expression of the genes related to lipogenesis (ACACA and FASN), lipolysis (CPT1A and PNPLA2), lipid transport (FABP4 and CD36) and lipid regulation (SREBP-1 and PPARG) and increased the lipid uptake. Silencing the TWEAK receptor (Fn14) in PC-3 cells confirmed the observed lipid metabolic effects, as shown by the downregulation of ACACA, FASN, CPT1A, PNPLA2, FABP4, CD36, SREBP-1 and PPARG expression, which was paralleled by a reduction of FASN, CPT1A and FABP4 protein expression. Specific-signaling inhibitor assays show that ERK1/2 and AKT (ser473) phosphorylation can regulate lipid metabolism-related genes in PCa cells, pointing to the AKT locus as a possible target for PCa. Overall, our data support sTWEAK/Fn14 axis as a potential therapeutic target for PCa.
Highlights
Prostate cancer (PCa) is the second-most commonly diagnosed cancer in men worldwide [1]
Serum insulin, HOMAIR, HDL-cholesterol, creatinine and total serum prostate-specific antigen (PSA) levels were all significantly higher in patients with PCa than in the controls (Table 1), whereas the opposite was seen for the serum Soluble tumor necrosis factor-like weak inducer of apoptosis (TWEAK) (sTWEAK) levels (Figure 1A)
To assess whether sTWEAK influences PCa cell metabolism, we examined for possible changes elicited by sTWEAK on the expression of the selected genes associated with glucose metabolism in two PCa cell lines (LNCaP and PC-3 cells) and a control, epithelial cell line (RWPE-1)
Summary
Prostate cancer (PCa) is the second-most commonly diagnosed cancer in men worldwide [1]. A central challenge in the management of PCa is discriminating between the indolent and aggressive disease, and the early detection of PCa is important to guide treatment strategies. In this context, the prostate-specific antigen (PSA) test, as well as the tumor, node, metastasis (TNM) classification and the Gleason score in prostate biopsies, are routinely used for predicting the prognosis and informing treatment decisions [2]. De novo lipogenesis relies on the enzymatic activities of ACLY (ATP citrate synthase), ACACA (acetyl-CoA carboxylase alpha) and FASN (fatty acid synthase), which generate diverse lipid species [3,4]
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