Serine Catabolism Regulates Mitochondrial Redox Control During Hypoxia

Overview

Journal Cancer Discov

Specialty Oncology

Date 2014 Sep 5

PMID 25186948

Citations 257

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

Affiliations

Soon will be listed here.

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.

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