Journal
CANCER RESEARCH
Volume 74, Issue 3, Pages 727-737Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-13-2584
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Funding
- National Natural Science Foundation of China [31171407, 81273201]
- Science and Technology Commission of Shanghai Municipality [12JC1400900]
- Shanghai Municipal Education Commission [14ZZ009]
- Excellent Youth Foundation of Chinese Academy of Sciences [KSCX2EW-Q-7]
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Myeloid-derived suppressor cells (MDSC) display an immature phenotype that may assume a classically activated (M1) or alternatively activated phenotype (M2) in tumors. In this study, we investigated metabolic mechanisms underlying the differentiation of MDSCs into M1 or M2 myeloid lineage and their effect on cancer pathophysiology. We found that SIRT1 deficiency in MDSCs directs a specific switch to M1 lineage when cells enter the periphery from bone marrow, decreasing the suppressive function in favor of a proinflammatory M1 phenotype associated with tumor cell attack. Glycolytic activation through the mTOR-hypoxia-inducible factor1a (HIF-1 alpha) pathway was required for differentiation to the M1 phenotype, which conferred protection against tumors. Our results define the essential nature of a SIRT1-mTOR/HIF-1 alpha glycolytic pathway in determining MDSC differentiation, with implications for metabolic reprogramming as a cancer therapeutic approach. (C) 2013 AACR.
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