Serine catabolism regulates mitochondrial redox control during hypoxia Journal Article
| Authors: | Ye, J.; Fan, J.; Venneti, S.; Wan, Y. W.; Pawel, B. R.; Zhang, J.; Finley, L. W. S.; Lu, C.; Lindsten, T.; Cross, J. R.; Qing, G.; Liu, Z.; Celeste Simon, M.; Rabinowitz, J. D.; Thompson, C. B. |
| Article Title: | Serine catabolism regulates mitochondrial redox control during hypoxia |
| 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 CO 2 and NH 4 + , 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. |
| Keywords: | immunohistochemistry; controlled study; human tissue; unclassified drug; human cell; major clinical study; flow cytometry; electron microscopy; cell death; cell viability; cell survival; reverse transcription polymerase chain reaction; breast cancer; gene expression; serine; hypoxia; correlation analysis; xenograft; neuroblastoma; myc protein; scoring system; immunoblotting; reactive oxygen metabolite; lactate dehydrogenase; real time polymerase chain reaction; upregulation; tissue microarray; tumor growth; mass fragmentography; homeostasis; bioinformatics; hypoxia inducible factor 1alpha; mitochondrion; catabolism; phosphoglycerate dehydrogenase; reduced nicotinamide adenine dinucleotide phosphate; phosphoglycerate kinase; human; article; glycine hydroxymethyltransferase; oxidation reduction potential; glycine hydroxymethyltransferase 2; lactate dehydrogenase a; phosphoglycerate kinase isoenzyme 1 |
| Journal Title: | Cancer Discovery |
| Volume: | 4 |
| Issue: | 12 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2014-12-01 |
| Start Page: | 1406 |
| End Page: | 1417 |
| Language: | English |
| DOI: | 10.1158/2159-8290.cd-14-0250 |
| PROVIDER: | scopus |
| PMCID: | PMC4258153 |
| PUBMED: | 25186948 |
| DOI/URL: | |
| Notes: | Export Date: 2 January 2015 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work