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Serum Levels of the Cytokine TWEAK Are Associated with Metabolic Status in Patients with Prostate Cancer and Modulate Cancer Cell Lipid Metabolism In Vitro.

ABSTRACT: 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.

SUBMITTER: Altuna-Coy A

PROVIDER: S-EPMC8465414 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The objective of this study was to evaluate the age-related changes in antioxidant status and the lipid metabolism of pigeon squabs (Columba livia), by determining the BW, antioxidant indices, serum lipid levels, lipid metabolism-related enzyme activities, lipid metabolism-related gene expression, and liver morphology in squabs. Ten squabs were randomly selected and sampled on the day of hatching (DOH), days 7 (D7), 14 (D14) and 21 (D21) post-hatch, respectively. The results showed that BW of squabs increased linearly from DOH to D21. The minimum fold of BW gain was observed in the phase from D14 to D21. Serum triglyceride and free fatty acid levels displayed linear and quadratic trends as age increased, with these maximum responses in D14. Serum low-density lipoprotein cholesterol level responded to age linearly and quadratically with the minimum in D14. Serum high-density lipoprotein cholesterol level and the ratio of high-density lipoprotein cholesterol to low-density lipoprotein cholesterol increased linearly with age, whereas the very low-density lipoprotein cholesterol level decreased linearly. The activities of glutathione peroxidase, catalase, and superoxide dismutase in liver displayed linear and quadratic trends as age increased, with these minimum responses in D14. Hepatic malondialdehyde concentration responded to age linearly and quadratically, with the maximum in D14. Activities of lipoprotein lipase, hepatic lipase, and 3-hydroxy-3-methyl glutaryl coenzyme A reductase in liver responded to age linearly and quadratically, with these minimum responses in D14. Hepatic hormone-sensitive lipase activity displayed linear and quadratic trends as age increased with the maximum in D14. Hepatic acetyl CoA carboxylase activity on D14 was significantly lower than squabs on DOH and D7. Hepatic carnitine palmitoyltransferase 1 mRNA expression responded to age linearly and quadratically, with minimum response in D14. Hepatic mRNA expression of acetyl CoA carboxylase and fatty acid synthetase increased linearly with age. Hepatic Oil-Red-O staining area displayed a quadratic trend as age increased, with the maximum response in D14. In conclusion, the phase from DOH to D14 was a crucial development stage for growth, antioxidant status and lipid metabolism in pigeon squabs. The results suggest it is better to take nutritional manipulation in squabs before D14.

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Serum Levels of the Cytokine TWEAK Are Associated with Metabolic Status in Patients with Prostate Cancer and Modulate Cancer Cell Lipid Metabolism In Vitro.

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