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.