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Cancer Discov. 2014 Dec;4(12):1406-17. doi: 10.1158/2159-8290.CD-14-0250. Epub 2014 Sep 3.

Serine catabolism regulates mitochondrial redox control during hypoxia.

Author information

1
Cancer Biology and Genetics Program and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
2
Lewis-Sigler Institute for Integrative Genomics and Department of Chemistry, Princeton University, Princeton, New Jersey.
3
Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas.
4
Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
5
Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, New York.
6
Provincial Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
7
Department of Pediatrics-Neurology, Baylor College of Medicine, Houston, Texas.
8
The Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine and Howard Hughes Medical Institute, Philadelphia, Pennsylvania.
9
Cancer Biology and Genetics Program and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York. thompsonc@mskcc.org.

Abstract

The de novo synthesis of the nonessential amino acid serine is often upregulated in cancer. In this study, we demonstrate that the serine catabolic enzyme, mitochondrial serine hydroxymethyltransferase (SHMT2), is induced when MYC-transformed cells are subjected to hypoxia. In mitochondria, SHMT2 can initiate the degradation of serine to CO2 and NH4+, resulting in net production of NADPH from NADP+. Knockdown of SHMT2 in MYC-dependent cells reduced cellular NADPH:NADP+ ratio, increased cellular reactive oxygen species, and triggered hypoxia-induced cell death. In vivo, SHMT2 suppression led to impaired tumor growth. In MYC-amplified neuroblastoma patient samples, there was a significant correlation between SHMT2 and hypoxia-inducible factor-1 α (HIF1α), and SHMT2 expression correlated with unfavorable patient prognosis. Together, these data demonstrate that mitochondrial serine catabolism supports tumor growth by maintaining mitochondrial redox balance and cell survival.

SIGNIFICANCE:

In this study, we demonstrate that the mitochondrial enzyme SHMT2 is induced upon hypoxic stress and is critical for maintaining NADPH production and redox balance to support tumor cell survival and growth.

PMID:
25186948
PMCID:
PMC4258153
DOI:
10.1158/2159-8290.CD-14-0250
[Indexed for MEDLINE]
Free PMC Article

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