Abstract
Mannose supplementation has emerged as a promising strategy to exploit the hidden vulnerabilities of cancer cells. However, the mannose-dependent effect on cellular functions remains unclear. Here, we investigated the collateral impact of mannose supplementation on the metastatic potential of osteosarcoma. Analysis of a paired osteosarcoma dataset showed significant upregulation of GPI in tumors compared with matched normal tissue, whereas other glycolysis- and mannose-metabolism genes showed non-significant upward trends. By using osteosarcoma cell lines, MG-63 carrying a pronounced epithelial-to-mesenchymal transition phenotype showed a dose-dependent inhibition of proliferation upon mannose supplementation. We also found that mannose-induced attenuation of cell growth was further enhanced, accompanied by marked reductions in migration and invasion ability. Consistently, qPCR analysis indicated that mannose supplementation downregulated key genes associated with metastasis. Collectively, our data reveal that mannose inhibits osteosarcoma not merely by dampening glycolysis but also by triggering, in part, MPI-linked mannose metabolism, which disrupts key drivers of motility-associated phenotypes. Together, these data show that pharmacologic mannose supplementation modulates cell growth- and motility-associated phenotypes in osteosarcoma cell models, accompanied by changes in epithelial-to-mesenchymal transition-associated transcripts.