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.
Academy of Orthopedics of Guangdong Province, The Third Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong 510630, P.R. China.
Xiaokai
X
Wang
Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.
Pinglin
P
Lai
Academy of Orthopedics of Guangdong Province, The Third Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong 510630, P.R. China.
Zhongmin
Z
Zhang
Academy of Orthopedics of Guangdong Province, The Third Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong 510630, P.R. China.
Minjun
M
Huang
Academy of Orthopedics of Guangdong Province, The Third Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong 510630, P.R. China.
Liang
L
Wang
Department of Orthopedics, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China.
Min
M
Yin
Academy of Orthopedics of Guangdong Province, The Third Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong 510630, P.R. China.
Dadi
D
Jin
Department of Orthopedics, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China.
Rongping
R
Zhou
Academy of Orthopedics of Guangdong Province, The Third Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong 510630, P.R. China.
Xiaochun
X
Bai
D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D002352:Carrier Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D055785:Gene Knockdown Techniques; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors*; D012516:Osteosarcoma / Q000378:metabolism / Q000473:pathology*; D011687:Purines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
D002352:Carrier Proteins; D007211:Indoles; D046912:Multiprotein Complexes; D011687:Purines; C492571:RICTOR protein, human; D034741:RNA, Small Interfering; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; C572919:PP242; D002945:Cisplatin; D020123:Sirolimus