Blocking glycine utilization inhibits multiple myeloma progression by disrupting glutathione balance

Metabolites in the tumor microenvironment are a critical factor for tumor progression. However, the lack of knowledge about the metabolic profile in the bone marrow (BM) microenvironment of multiple myeloma (MM) limits our understanding of MM progression. Here, we show that the glycine concentration in the BM microenvironment is elevated due to bone collagen degradation mediated by MM cell-secreted matrix metallopeptidase 13 (MMP13), while the elevated glycine level is linked to MM progression. MM cells utilize the channel protein solute carrier family 6 member 9 (SLC6A9) to absorb extrinsic glycine subsequently involved in the synthesis of glutathione (GSH) and purines. Inhibiting glycine utilization via SLC6A9 knockdown or the treatment with betaine suppresses MM cell proliferation and enhances the effects of bortezomib on MM cells. Together, we identify glycine as a key metabolic regulator of MM, unveil molecular mechanisms governing MM progression, and provide a promising therapeutic strategy for MM treatment. The bone tumour microenvironment plays an essential role in multiple myeloma (MM) development. Here, the authors show that bone collagen degradation provides glycine to support MM progression through glutathione and purine synthesis.

Automated summary

This study reveals that the elevated glycine level in the bone marrow microenvironment of multiple myeloma is associated with MM progression, and MM cells utilize the SLC6A9 protein to absorb glycine for the synthesis of glutathione and purines.