A novel mechanism of mTORC1-mediated serine/glycine metabolism in osteosarcoma development.
Osteosarcoma is the major malignant primary bone cancer in children and adolescents, which is highly aggressive with frequent acquisition of chemoresistance phenotypes. Although much progress has been made, mechanisms of osteosarcoma rapid growth and chemoresistance are still not well elucidated. Generally, alternated metabolic characterization has been proposed to be a hallmark of cancer, yet it is lack of a systematic characterization of cancer metabolic networks. In the present study, we aim to characterize osteosarcoma metabolism and key regulators to reveal mechanisms of how osteosarcoma grows and resists apoptosis under stress conditions. The results demonstrate that mTORC1 pathway is hyperactivated in clinical osteosarcoma samples. However, inhibition of mTORC1 may not be enough to induce significant death of osteosarcoma cells. Results of GC-TOFMS suggested that inhibition of mTORC1 reduce one-carbon amino acids, serine and glycine, in osteosarcoma cells. Moreover, mTORC1 regulates serine/glycine de novo synthesis via modulating glycolysis and serine/glycine synthesis gene expressions. Further, mTORC1/serine/glycine metabolic axis promotes osteosarcoma proliferation and antioxidant ability to environmental stress, which finally leads to cell survival. Our results identify a novel mechanism of mTORC1-mediated serine/glycine metabolism as a significant protective system in osteosarcoma cells.
Department of Orthopaedics, The First Affiliated Hospital of Harbin Medical University, No. 23 Post Street, Nangang District, Harbin 150001, China.
Da-Wei
DW
Wang
Department of Orthopedics, The Fourth Affiliated Hospital of Harbin Medical University, No. 37 Yiyuan Street, Nangang District, Harbin 150001, China.
Liwen
L
Wu
Department of Orthopaedics, The First Affiliated Hospital of Harbin Medical University, No. 23 Post Street, Nangang District, Harbin 150001, China.
Yang
Y
Cao
Department of Orthopaedics, The First Affiliated Hospital of Harbin Medical University, No. 23 Post Street, Nangang District, Harbin 150001, China.
Lei
L
Yang
Department of Orthopaedics, The First Affiliated Hospital of Harbin Medical University, No. 23 Post Street, Nangang District, Harbin 150001, China.
Wei
W
Liu
Department of Orthopaedics, The First Affiliated Hospital of Harbin Medical University, No. 23 Post Street, Nangang District, Harbin 150001, China.
Xiao-Qiang
XQ
E
Department of Orthopedics, The Second Affiliated Hospital of Harbin Medical University, No. 246 Xuefu Road, Nangang District, Harbin 150001, China.
Guangrong
G
Ji
Department of Orthopaedics, The First Affiliated Hospital of Harbin Medical University, No. 23 Post Street, Nangang District, Harbin 150001, China. Electronic address: zhenggangbi08@126.com.
Zheng-Gang
ZG
Bi
D017209:Apoptosis; D002244:Carbon / Q000378:metabolism; D063646:Carcinogenesis / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005998:Glycine / Q000378:metabolism*; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000378:metabolism*; D008954:Models, Biological; D012516:Osteosarcoma / Q000378:metabolism* / Q000473:pathology*; D010084:Oxidation-Reduction; D012694:Serine / Q000378:metabolism*; D015398:Signal Transduction
D012694:Serine; D002244:Carbon; D000076222:Mechanistic Target of Rapamycin Complex 1; D005998:Glycine
Antioxidant; Osteosarcoma; Proliferation; Serine/glycine; mTORC1