期刊
ACS CHEMICAL BIOLOGY
卷 10, 期 2, 页码 510-516出版社
AMER CHEMICAL SOC
DOI: 10.1021/cb500683c
关键词
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资金
- NIH [1R01CA163591, P50GM071508, P30CA14051]
- NSF
- AACR
- Burroughs Wellcome Fund
- Howard Hughes Medical Institute (HHMI) international student research fellowship
- Cancer Research UK [Test_AK, Test_Training1] Funding Source: researchfish
Human D-3-phosphoglycerate dehydrogenase (PHGDH), the first enzyme in the serine biosynthetic pathway, is genomically amplified in tumors including breast cancer and melanoma. In PHGDH-amplified cancer cells, knockdown of PHGDH is not fully rescued by exogenous serine, suggesting possible additional growth-promoting roles for the enzyme. Here we show that, in addition to catalyzing oxidation of 3-phosphoglycerate, PHGDH catalyzes NADH-dependent reduction of alpha-ketoglutarate (AKG) to the oncometabolite D-2-hydroxyglutarate (D-2HG). Knockdown of PHGDH decreased cellular 2HG by approximately 50% in the PHGDH-amplified breast cancer cell lines MDA-MB-468 (normal concentration 93 mu M) and BT-20 (normal concentration 35 mu M) and overexpression of PHGDH increased cellular 2HG by over 2-fold in non-PHGDH-amplified MDA-MB-231 breast cancer cells, which normally display very low PHGDH expression. The reduced 2HG level in PHGDH knockdown cell lines can be rescued by PHGDH re-expression, but not by a catalytically inactive PHGDH mutant. The initial connection between cancer and D-2HG involved production of high levels of D-2HG by mutant isocitrate dehydrogenase. More recently, however, elevated D-2HG has been observed in breast cancer tumors without isocitrate dehydrogenase mutation. Our results suggest that PHGDH is one source of this d-2HG.
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