Targeted inhibition of mTORC2 prevents osteosarcoma cell migration and promotes apoptosis.

Dysregulation of mammalian target of rapamycin (mTOR) signaling often occurs in many human malignant diseases, making it a potential target in the treatment of cancer. However, the effects of specifically targeted inhibition of mammalian target of rapamycin complex 2 (mTORC2) on osteosarcoma have not been reported. Three types of osteosarcoma cell lines (MG63/U2OS/Saos-2) were used in this study. Inhibition of mTORC2 was carried out by mTOR inhibitor PP242 and targeted siRNA. The anti-migration effect was evaluated through wound healing and Transwell assays. Osteosarcoma cells were either treated independently by inhibition of mTORC2 or in combination with cisplatin, and apoptosis was evaluated by staining with propidium iodide; PARP and caspase 7 expression levels were evaluated. Targeting of mTORC2 either by kinase inhibitor or rictor knockdown promoted cisplatin-induced apoptosis, but inhibition of mTORC1 either by rapamycin or raptor knockdown did not promote cisplatin-induced apoptosis. Furthermore, inhibition of mTORC2 but not mTORC1 effectively prevented osteosarcoma cell migration. These results suggest that agents that inhibit mTORC2 have advantages over mTORC1 inhibitors in the treatment of osteosarcoma. The present study provides a strong rationale for testing the use of mTORC1/2 inhibitors or the combination of mTORC1/2 inhibitors and cisplatin in the treatment of osteosarcoma.