The Antimetastatic Effect On Prostate Cancer By Targeting Class ? PI3K Isoforms And The Mechanism

Objective: To study the antimetastatic effect and mechanism on prostate cancer in vitro and in vivo by targeting class I PI3 K isoforms,and to elucidate the PI3 K isoforms,which play a key role in the metastasis of prostate cancer,and therefore providing potential strategy for the treatment of prostate cancer.Methods: 1.The effects of PI3 K isoform specific inhibitors on the migration ability and invasion ability of PC3 and DU145 cells were investigated by Transwell migration assay and Transwell invasion assay.2.The effects of PI3K? and d isoform specific inhibitors on the expression and phosphorylation of metastasis-related signal protein Akt and its downstream protein Integrin?1 in PC3 and DU145 cells were investigated by Western blot analysis.3.The expression of PI3K? and d isoforms in PC3 and DU145 cells were further examined by si RNA transfection,which further demonstrated the role of each isoform in the migration of prostate cancer cells.4.The bone mass efficacy of PI3K? and d isoform specific inhibitors on model of bone metastasis in vivo was studied by micro CT analysis.5.The effects of PI3K? and d isoform specific inhibitors on the metastasis of prostate cancer were studied by HE staining,TRAP staining and Macneal's staining.Results: 1.PI3 K isoform specific inhibitors exhibited potential effect on tumor metastasis in vitro,they inhibited the migration and invasion of PC3 and DU145 cells,moreover,compared with the IC50 value of kinase inhibitory activity,PI3K? and d isoforms might be required for both cells migration and invasion,while PI3K? and ? isoforms might be redundant;2.PI3K? and d isoform specific inhibitors significantly decreased the phosphorylation level of Akt and downstream protein Integrin?1 in PC3 and DU145 cells in a dose-dependent manner;3.The phosphorylation of Akt in,and the migration of,PC3 and DU145 cells were inhibited by silencing PIK3 CB or PIK3 CD with si RNA;4.PI3K? and d isoform specific inhibitors effectively improved bone mass on model of prostate cancer bone metastasis in nude mice,increased bone mineral density;5.PI3K? and d isoform specific inhibitors inhibited the bone metastasis of prostate cancer cells,reduced the number of osteoclasts,increased the number of osteoblasts trend.Conclusions: 1.In the four PI3 K isoform specific inhibitors,PI3K? and d isoform specific inhibitors had a strong ability to inhibit the migration and invasion of prostate cancer cells at low concentration,and showed potential anti-tumor metastasis activity in vitro.2.PI3K? and d isoform specific inhibitors and si RNA reduced the phosphorylation of Akt in prostate cancer cells at the concentration of anti-prostate cancer cell migration,suggesting that they might inhibit the migration and invasion of prostate cancer cells through PI3K/Akt signaling pathway.3.PI3K? and d isoform specific inhibitors significantly inhibited the bone metastasis of prostate cancer cells,and improved bone microenvironment by reducing osteoclast bone resorption and increasing osteoblast bone formation,suggesting that these two isoforms play a key role in the metastasis of prostate cancer.