Serine catabolism regulates mitochondrial redox control during hypoxia.

Abstract

UNLABELLED:

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.

• Authors: Jiangbin Ye, Jing Fan, Sriram Venneti, Ying-Wooi Wan, Bruce R Pawel, Ji Zhang, Lydia W S Finley, Chao Lu, Tullia Lindsten, Justin R Cross, Guoliang Qing, Zhandong Liu, M Celeste Simon, Joshua D Rabinowitz, Craig B Thompson
• Journal: Cancer discovery (Cancer Discov) Vol. 4 Issue 12 Pg. 1406-17 (Dec 2014) ISSN: 2159-8290 [Electronic] United States
• PMID: 25186948 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Hypoxia-Inducible Factor 1, alpha Subunit
• Reactive Oxygen Species
• Serine
• Phosphoglycerate Dehydrogenase
• Glycine Hydroxymethyltransferase
• SHMT protein, human

Topics

• Animals
• Base Sequence
• Cell Line, Tumor
• Cell Survival (genetics)
• Disease Models, Animal
• Gene Amplification
• Gene Expression
• Gene Knockdown Techniques
• Genes, myc
• Glycine Hydroxymethyltransferase (chemistry, genetics, metabolism)
• Heterografts
• Homeostasis
• Humans
• Hypoxia (genetics, metabolism)
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Mice
• Mitochondria (genetics, metabolism)
• Models, Biological
• Molecular Sequence Data
• Neoplasms (genetics, metabolism, pathology)
• Oxidation-Reduction
• Phosphoglycerate Dehydrogenase (genetics, metabolism)
• Promoter Regions, Genetic
• Reactive Oxygen Species (metabolism)
• Serine (metabolism)
• Tumor Burden (genetics)