期刊
BRITISH JOURNAL OF HAEMATOLOGY
卷 190, 期 1, 页码 52-66出版社
WILEY
DOI: 10.1111/bjh.16503
关键词
multiple myeloma; bortezomib; GSH; PHGDH; serine
类别
资金
- National Natural Science Foundation of China [81570205, 81630007, 81800209, 81974010]
- Strategic Priority Research Program of Central South University [ZLXD2017004]
- Ministry of Science and Technology of China [2018YFA0107800]
- Open Sharing Fund for the Large-scale Instruments And Equipments of Central South University [CSUZC201949, CSUZC201948]
- China Postdoctoral Science Foundation [2018M640762]
- Postdoctoral Science Foundation of Central South University [198465]
- Hunan Province Natural Science Foundation of China [2019JJ50838]
- Hunan Provincial Innovation Foundation for Postgraduates [CX20190233]
- Fundamental Research Funds for the Central Universities of Central South University [2019zzts177, 2019zzts1010, 2019zzts716, 2019zzts717, 2018zzts079]
The serine synthesis pathway (SSP) is active in multiple cancers. Previous study has shown that bortezomib (BTZ) resistance is associated with an increase in the SSP in multiple myeloma (MM) cells; however, the underlying mechanisms of SSP-induced BTZ resistance remain unclear. In this study, we found that phosphoglycerate dehydrogenase (PHGDH), the first rate-limiting enzyme in the SSP, was significantly elevated in CD138(+) cells derived from patients with relapsed MM. Moreover, high PHGDH conferred inferior survival in MM. We also found that overexpression of PHDGH in MM cells led to increased cell growth, tumour formation, and resistance to BTZ in vitro and in vivo, while inhibition of PHGDH by short hairpin RNA or NCT-503, a specific inhibitor of PHGDH, inhibited cell growth and BTZ resistance in MM cells. Subsequent mechanistic studies demonstrated PHGDH decreased reactive oxygen species (ROS) through increasing reduced glutathione (GSH) synthesis, thereby promoting cell growth and BTZ resistance in MM cells. Furthermore, adding GSH to PHGDH silenced MM cells reversed S phase arrest and BTZ-induced cell death. These findings support a mechanism in which PHGDH promotes proliferation and BTZ resistance through increasing GSH synthesis in MM cells. Therefore, targeting PHGDH is a promising strategy for MM therapy.
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