A lactate-induced response to hypoxia - PubMed

Affiliations

• PMID: 25892225
• DOI: 10.1016/j.cell.2015.03.011

Free article

A lactate-induced response to hypoxia

Dong Chul Lee et al. Cell. 2015.

Free article

Abstract

Organisms must be able to respond to low oxygen in a number of homeostatic and pathological contexts. Regulation of hypoxic responses via the hypoxia-inducible factor (HIF) is well established, but evidence indicates that other, HIF-independent mechanisms are also involved. Here, we report a hypoxic response that depends on the accumulation of lactate, a metabolite whose production increases in hypoxic conditions. We find that the NDRG3 protein is degraded in a PHD2/VHL-dependent manner in normoxia but is protected from destruction by binding to lactate that accumulates under hypoxia. The stabilized NDRG3 protein binds c-Raf to mediate hypoxia-induced activation of Raf-ERK pathway, promoting angiogenesis and cell growth. Inhibiting cellular lactate production abolishes the NDRG3-mediated hypoxia responses. Our study, therefore, elucidates the molecular basis for lactate-induced hypoxia signaling, which can be exploited for the development of therapies targeting hypoxia-induced diseases.

Similar articles

• NDRG3-mediated lactate signaling in hypoxia.

  Park KC, Lee DC, Yeom YI. Park KC, et al. BMB Rep. 2015 Jun;48(6):301-2. doi: 10.5483/bmbrep.2015.48.6.080. BMB Rep. 2015. PMID: 25936780 Free PMC article.

• Gambogic acid inhibits angiogenesis through inhibiting PHD2-VHL-HIF-1α pathway.

  Lu N, Hui H, Yang H, Zhao K, Chen Y, You QD, Guo QL. Lu N, et al. Eur J Pharm Sci. 2013 May 13;49(2):220-6. doi: 10.1016/j.ejps.2013.02.018. Epub 2013 Mar 15. Eur J Pharm Sci. 2013. PMID: 23501055

• Hypoxia-inducible factor-1 (HIF-1) promotes its degradation by induction of HIF-alpha-prolyl-4-hydroxylases.

  Marxsen JH, Stengel P, Doege K, Heikkinen P, Jokilehto T, Wagner T, Jelkmann W, Jaakkola P, Metzen E. Marxsen JH, et al. Biochem J. 2004 Aug 1;381(Pt 3):761-7. doi: 10.1042/BJ20040620. Biochem J. 2004. PMID: 15104534 Free PMC article.

• Hypoxia-induced erythropoietin production: a paradigm for oxygen-regulated gene expression.

  Stockmann C, Fandrey J. Stockmann C, et al. Clin Exp Pharmacol Physiol. 2006 Oct;33(10):968-79. doi: 10.1111/j.1440-1681.2006.04474.x. Clin Exp Pharmacol Physiol. 2006. PMID: 17002676 Review.

• Cellular oxygen sensing need in CNS function: physiological and pathological implications.

  Acker T, Acker H. Acker T, et al. J Exp Biol. 2004 Aug;207(Pt 18):3171-88. doi: 10.1242/jeb.01075. J Exp Biol. 2004. PMID: 15299039 Review.

Cited by

• Targeting Lactate: An Emerging Strategy for Macrophage Regulation in Chronic Inflammation and Cancer.

  Jiang R, Ren WJ, Wang LY, Zhang W, Jiang ZH, Zhu GY. Jiang R, et al. Biomolecules. 2024 Sep 24;14(10):1202. doi: 10.3390/biom14101202. Biomolecules. 2024. PMID: 39456135 Free PMC article. Review.

• Lactate modulation of immune responses in inflammatory versus tumour microenvironments.

  Certo M, Tsai CH, Pucino V, Ho PC, Mauro C. Certo M, et al. Nat Rev Immunol. 2021 Mar;21(3):151-161. doi: 10.1038/s41577-020-0406-2. Epub 2020 Aug 24. Nat Rev Immunol. 2021. PMID: 32839570 Review.

• How Reciprocal Interactions Between the Tumor Microenvironment and Ion Transport Proteins Drive Cancer Progression.

  Elingaard-Larsen LO, Rolver MG, Sørensen EE, Pedersen SF. Elingaard-Larsen LO, et al. Rev Physiol Biochem Pharmacol. 2022;182:1-38. doi: 10.1007/112_2020_23. Rev Physiol Biochem Pharmacol. 2022. PMID: 32737753 Review.

• Transcriptional control of kidney cancer.

  Sanchez DJ, Simon MC. Sanchez DJ, et al. Science. 2018 Jul 20;361(6399):226-227. doi: 10.1126/science.aau4385. Science. 2018. PMID: 30026212 Free PMC article. No abstract available.

• Regulatory Role of Endothelial PHD2 in the Hepatic Steatosis.

  Zhou LY, Zeng H, Wang S, Chen JX. Zhou LY, et al. Cell Physiol Biochem. 2018;48(3):1003-1011. doi: 10.1159/000491968. Epub 2018 Jul 23. Cell Physiol Biochem. 2018. PMID: 30036883 Free PMC article.

Publication types

MeSH terms

Substances

LinkOut - more resources

• Full Text Sources

  • Elsevier Science

• Other Literature Sources

  • The Lens - Patent Citations Database

• Molecular Biology Databases

  • NIAID Data Ecosystem - Find datasets on Infectious and Immune-mediated Diseases
  • PhosphoSitePlus

• Research Materials

  • NCI CPTC Antibody Characterization Program

• Miscellaneous

  • NCI CPTAC Assay Portal