TXNIP inhibits the progression of osteosarcoma through DDIT4-mediated mTORC1 suppression.

Abstract

Osteosarcoma (OS) is the most common primary malignant bone tumor in adolescents and children. The pathogenesis of this disease is complex and the mechanisms involved have not been fully elucidated. Thioredoxin-interacting protein (TXNIP), as a member of the α-rhodopsin inhibitory protein family, can combine with thioredoxin to inhibit its antioxidant function. This process inhibits glucose absorption and metabolic rearrangement necessary for the regulation of cellular growth. In recent years, TXNIP has emerged as a new candidate target for tumors. However, the biological function and role of TXNIP in OS remains unclear. This study confirmed the low expression of TXNIP in OS tissues and cells, which was significantly related to the poor survival rate and clinical characteristics of patients with OS. Various cell phenotype experiments have shown that TXNIP inhibits the proliferation, migration, and invasion of OS cells, and promotes their apoptosis. Further studies found that the tumor suppressor effect of TXNIP was mediated by upregulating DNA damage-inducible transcript 4 (DDIT4) and inhibiting the phosphorylation of mechanistic target of rapamycin complex 1 (mTORC1) downstream substrate S6. Based on the above, our study explored the key role of TXNIP/DDIT4/mTORC1 suppression as a regulatory axis in the progression of OS, and laid the foundation for precise targeted therapy for OS.