Gambogic acid inhibits TNF-α-induced invasion of human prostate cancer PC3 cells in vitro through PI3K/Akt and NF-κB signaling pathways

• Published in: Acta pharmacologica Sinica 2012-04, Vol.33 (4), p.531-541
• Main Authors: Lü, Lei, Tang, Dong, Wang, Liang, Huang, Lu-qi, Jiang, Guo-song, Xiao, Xing-yuan, Zeng, Fu-qing
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents, Phytogenic - pharmacology; Biomedical and Life Sciences; Biomedicine; Cell Line, Tumor; Cell Movement - drug effects; Garcinia - chemistry; Humans; Immunology; Internal Medicine; Male; Medical Microbiology; Neoplasm Invasiveness - immunology; Neoplasm Invasiveness - prevention & control; NF-kappa B - immunology; Original; original-article; Pharmacology/Toxicology; Phosphatidylinositol 3-Kinases - immunology; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - immunology; Prostatic Neoplasms - pathology; Proto-Oncogene Proteins c-akt - immunology; Signal Transduction; Tumor Necrosis Factor-alpha - immunology; Vaccine; Xanthones - pharmacology
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/aps.2011.180

Aim: To investigate the mechanisms underlying the inhibitory effect of gambogic acid (GA) on TNF-α-induced metastasis of human prostate cancer PC3 cells in vitro . Methods: TNF-α-mediated migration and invasion of PC3 cells was examined using migration and invasion assays, respectively. NF-κB transcriptional activity and nuclear translocation were analyzed with luciferase reporter gene assays, immunofluorescence assays and Western blots. The ability of p65 to bind the promoter of Snail, an important mesenchymal molecular marker, was detected using a chromatin immunoprecipitation (ChIP) assay. After treatment with Snail-specific siRNA, the expression of invasiveness-associated genes was measured using quantitative real-time PCR and Western blot. Results: GA significantly inhibited the viability of PC3 cells at 1–5 μmol/L, but did not produce cytotoxic effect at the concentrations below 0.5 μmol/L. GA (0.125–0.5 μmol/L) dose-dependently inhibited the migration and invasion of PC3 cells induced by TNF-α (10 ng/mL). Moreover, the TNF-α-mediated activation of phosphatidylinositol-3-OH kinase/protein kinase B (PI3K/Akt) and NF-κB pathways was suppressed by GA (0.5 μmol/L). Furthermore, this anti-invasion effect of GA was associated with regulation of Snail. Snail expression was significantly down-regulated by treatment with GA (0.5 μmol/L) in the TNF-α-stimulated PC3 cells. Conclusion: GA inhibits TNF-α-induced invasion of PC3 cells via inactivation of the PI3K/Akt and NF-κB signaling pathways, which may offer a novel approach for the treatment of human prostate cancer.