Blocking glycine utilization inhibits multiple myeloma progression by disrupting glutathione balance

Jiliang Xia, Jingyu Zhang, Xuan Wu, Wanqing Du, Yinghong Zhu, Xing Liu, Zhenhao Liu, Bin Meng, Jiaojiao Guo, Qin Yang, Yihui Wang, Qinglin Wang, Xiangling Feng, Guoxiang Xie, Yi Shen, Yanjuan He, Juanjuan Xiang, Minghua Wu, Gang An, Lugui Qiu, Wei Jia and Wen Zhou ()
Additional contact information
Jiliang Xia: Central South University
Jingyu Zhang: Central South University
Xuan Wu: Central South University
Wanqing Du: Central South University
Yinghong Zhu: Central South University
Xing Liu: Central South University
Zhenhao Liu: Central South University
Bin Meng: Central South University
Jiaojiao Guo: Central South University
Qin Yang: Central South University
Yihui Wang: Central South University
Qinglin Wang: Hunan Normal University School of Medicine
Xiangling Feng: Central South University
Guoxiang Xie: Human Metabolomics Institute, Inc
Yi Shen: Central South University
Yanjuan He: Central South University
Juanjuan Xiang: Central South University
Minghua Wu: Central South University
Gang An: Chinese Academy of Medical Science & Peking Union Medical College
Lugui Qiu: Chinese Academy of Medical Science & Peking Union Medical College
Wei Jia: Hong Kong Baptist University, Kowloon Tong
Wen Zhou: Central South University

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-31248-w

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