| Summary: | 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 (<i>SLC2A4</i> and <i>SLC2A1</i>), but significantly reduced the expression of glucose metabolism-related genes (<i>PFK</i>, <i>HK1</i> and <i>PDK4</i>) in PCa cells. The sTWEAK stimulation of PC-3 cells significantly increased the expression of the genes related to lipogenesis (<i>ACACA</i> and <i>FASN</i>), lipolysis (<i>CPT1A</i> and <i>PNPLA2</i>), lipid transport (<i>FABP4</i> and <i>CD36</i>) and lipid regulation (<i>SREBP-1</i> and <i>PPARG</i>) 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 <i>ACACA</i>, <i>FASN</i>, <i>CPT1A</i>, <i>PNPLA2</i>, <i>FABP4</i>, <i>CD36</i>, <i>SREBP</i>-<i>1</i> and <i>PPARG</i> expression, which was paralleled by a reduction of <i>FASN</i>, <i>CPT1A</i> and <i>FABP4</i> 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.
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