2. Academic Validation
  3. Deprivation of methionine inhibits osteosarcoma growth and metastasis via C1orf112-mediated regulation of mitochondrial functions

Deprivation of methionine inhibits osteosarcoma growth and metastasis via C1orf112-mediated regulation of mitochondrial functions

  • Cell Death Dis. 2024 May 20;15(5):349. doi: 10.1038/s41419-024-06727-1.
Xindan Zhang 1,  Zhenggang Zhao 1,  Xuepeng Wang 1,  Shiwei Zhang 1,  Zilong Zhao 1,  Wenbin Feng 1,  Lijun Xu 1,  Junhua Nie 2,  Hong Li 3,  Jia Liu 2,  Gengmiao Xiao 1,  Yu Zhang 4,  Haomiao Li 5,  Ming Lu 5,  Jialuo Mai 6,  Sujin Zhou 7,  Allan Z Zhao 8,  Fanghong Li 9
Affiliations

Affiliations

  • 1 The School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, China.
  • 2 South China University of Technology School of Medicine, Guangzhou, China.
  • 3 Biomedical Laboratory, Guangzhou Jingke Life Science Institute, Guangzhou, China.
  • 4 Department of Orthopedic Oncology, Guangdong Provincial People's Hospital Affiliated to South China University of Technology School of Medicine, Guangzhou, China.
  • 5 Department of Musculoskeletal Oncology, Center for Orthopedic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
  • 6 Guangzhou Sinogen Pharmaceutical Co., Ltd., Guangzhou, Guangdong Province, China.
  • 7 The School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, China. zhousj@gdut.edu.cn.
  • 8 The School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, China. azzhao@gdut.edu.cn.
  • 9 The School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, China. fli@gdut.edu.cn.
PMID: 38769167 DOI: 10.1038/s41419-024-06727-1
Abstract

Osteosarcoma is a malignant bone tumor that primarily inflicts the youth. It often metastasizes to the lungs after chemotherapy failure, which eventually shortens patients' lives. Thus, there is a dire clinical need to develop a novel therapy to tackle osteosarcoma metastasis. Methionine dependence is a special metabolic characteristic of most malignant tumor cells that may offer a target pathway for such therapy. Herein, we demonstrated that methionine deficiency restricted the growth and metastasis of cultured human osteosarcoma cells. A genetically engineered Salmonella, SGN1, capable of overexpressing an L-methioninase and hydrolyzing methionine led to significant reduction of methionine and S-adenosyl-methionine (SAM) specifically in tumor tissues, drastically restricted the growth and metastasis in subcutaneous xenograft, orthotopic, and tail vein-injected metastatic models, and prolonged the survival of the model Animals. SGN1 also sharply suppressed the growth of patient-derived Organoid and xenograft. Methionine restriction in the osteosarcoma cells initiated severe mitochondrial dysfunction, as evident in the dysregulated gene expression of respiratory chains, increased mitochondrial ROS generation, reduced ATP production, decreased basal and maximum respiration, and damaged mitochondrial membrane potential. Transcriptomic and molecular analysis revealed the reduction of C1orf112 expression as a primary mechanism underlies methionine deprivation-initiated suppression on the growth and metastasis as well as mitochondrial functions. Collectively, our findings unraveled a molecular linkage between methionine restriction, mitochondrial function, and osteosarcoma growth and metastasis. A pharmacological agent, such as SGN1, that can achieve tumor specific deprivation of methionine may represent a promising modality against the metastasis of osteosarcoma and potentially other types of sarcomas as well.

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