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

作者：Xindan Zhang, Zhenggang Zhao, Xuepeng Wang, Shiwei Zhang, Zilong Zhao, Wenbin Feng, Lijun Xu, Jun‐Hua Nie, Hong Li, Jia Liu, Jia Liu, Gengmiao Xiao, Yu Zhang, Ming‐Chi Lu, Haomiao Li, Ming Lu, Jialuo Mai, Sujin Zhou, A. Zhao, Fanghong Li · 发表于：Cell Death and Disease · 年份：2024 · DOI：10.1038/s41419-024-06727-1 · 被引用次数：20 · 研究领域：Cancer Research and Treatments、Nanoplatforms for cancer theranostics、Graphene and Nanomaterials Applications

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 suppressio...