Phosphatidylinositol 3-kinase β and δ isoforms play key roles in metastasis of prostate cancer DU145 cells

What is it about?

Since metastasis is the main cause of lethality of prostate cancer, inhibition of metastasis is expected to be a promising approach for prostate cancer therapy. Class I phosphatidylinositol 3-kinases (PI3K), which contain four isoforms α, β, δ and γ, are known to play important roles in cancer growth and metastasis. However, the respective role of each PI3K isoform in cancer cell migration and invasion remains unknown. Aiming to elucidate the respective role of the 4 PI3K isoforms, we investigated the change in migratory and invasive ability of DU145 cells after treatment with 6 PI3K isoform specific inhibitors. Both migration and invasion of DU145 cells were potently blocked by each of the PI3Kβ inhibitors and PI3Kδ inhibitors, while not obviously affected by PI3Kα inhibitor or PI3Kγ inhibitor. The results suggest that PI3Kβ and PI3Kδ play key roles in prostate cancer cell migration, while PI3Kα and PI3Kγ might be redundant. Oral administration of PI3Kβ inhibitor GSK2636771 and PI3Kδ inhibitor CAL101 inhibited bone metastasis of DU145 cells, with improved bone structure and bone mineral density which were analyzed by microCT. Tissue staining indicated reduction of metastatic DU145 cells and osteoclasts in the bones of GSK2636771 and CAL101 treated mice, compared with the non-treated group. In conclusion, our result indicated the distinct roles of 4 PI3K isoforms in migration of prostate cancer DU145 cells, and demonstrated the in vitro and in vivo anti-metastatic effect of PI3K-isoform specific inhibitors, most of which are in clinical trials.

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