Blocking glycine utilization inhibits multiple myeloma progression by disrupting glutathione balance

Abstract

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.

Intestinal Klebsiella pneumoniae Contributes to Pneumonia by Synthesizing Glutamine in Multiple Myeloma

“…The role of diet in determining gut microbiota has been studied [ 33 ]. As previously reported by our work, the elevation of glycine in the bone marrow, which is due to bone collagen degradation and exogenous dietary intake, contributes to MM progression [ 17 ]. In turn, NH 4 + , produced by nitrogen resources, was accumulated in the intestine, and then altered the intestinal bacterial composition, resulting in the preferential proliferation of nitro-recycling bacteria ( K. pneumonia ).…”

“…All animal experiments were designed and conducted to conform to the guidelines of the Institutional Animal Care and local veterinary office and ethics committee of Central South University, China (animal experimental license: CSU-2022-0256) under an approved protocol. The luciferase-expressing 5TGM1 MM cells (1 × 10 6 cells in 200 μL PBS per mouse) were injected into 6-week-old C57BL/KaLwRij mice to build a 5TGM1 MM mouse model (dubbed “5TGM1 MM mice”) as reported before [ 16 , 17 ]. For Figure 1 , female mice were adopted, while for the other in vivo experiment, male mice were utilized.…”

“…Targeted metabolomics assays of peripheral blood (PB) plasma were performed by using the Q300 Metabolite Assay Kit (Human Metabolomics Institute, Inc. Shenzhen, China), as previously published [ 17 , 20 ]. The resulting datasets were analyzed by the SIMCA-P 14.1 software (Sartorius Stedim Biotech, Germany) package and MetaboAnalyst 5.0 online software ( ).…”

“…Differential metabolites ( p < 0.05) were defined. In addition, measurements of differential metabolites were performed utilizing high-performance liquid chromatography (HPLC), as described previously [ 17 , 21 ].…”

“…In the same study, we observed that enriched K. pneumonia promoted MM progression via de novo synthesis of glutamine in vivo. In addition, in another study of our recent work, glycine was identified as a key metabolic regulator of MM, unveiling the role of host metabolism in MM [ 17 ]. These discoveries in the impact of the gut microbiome and host metabolism on MM can thereby have considerable implications for the possible association between pneumonia in MM and gut microbiota.…”