LDHA in Neuroblastoma Is Associated with Poor Outcome and Its Depletion Decreases Neuroblastoma Growth Independent of Aerobic Glycolysis.

Abstract

Purpose: To investigate whether lactate dehydrogenase A (LDHA), an important component of the LDH tetramer crucial for aerobic glycolysis, is associated with patient outcome and constitutes a therapeutic target in neuroblastoma (NB).Experimental Design: Expression of LDHA mRNA and protein was determined in 709 and 110 NB patient samples, respectively, and correlated with survival and risk factors. LDHA and LDHB were depleted in human NB cell lines by CRISPR/Cas9 and shRNA, respectively, and aerobic glycolysis, clonogenicity, and tumorigenicity were determined. Expression of LDHA in relation to MYCN was measured in NB cell lines and in the TH-MYCN NB mouse model.Results: Expression of LDHA, both on the mRNA and the protein level, was significantly and independently associated with decreased patient survival. Predominant cytoplasmic localization of LDHA protein was associated with poor outcome. Amplification and expression of MYCN did not correlate with expression of LDHA in NB cell lines or TH-MYCN mice, respectively. Knockout of LDHA inhibited clonogenicity, tumorigenicity, and tumor growth without abolishing LDH activity or significantly decreasing aerobic glycolysis. Concomitant depletion of LDHA and the isoform LDHB ablated clonogenicity while not abrogating LDH activity or decreasing aerobic glycolysis. The isoform LDHC was not expressed.Conclusions: High expression of LDHA is independently associated with outcome of NB, and NB cells can be inhibited by depletion of LDHA or LDHB. This inhibition appears to be unrelated to LDH activity and aerobic glycolysis. Thus, investigations of inhibitory mechanisms beyond attenuation of aerobic glycolysis are warranted, both in NB and normal cells. Clin Cancer Res; 24(22); 5772-83. ©2018 AACR.

• Authors: Carmen Dorneburg, Matthias Fischer, Thomas F E Barth, Wolfgang Mueller-Klieser, Barbara Hero, Judith Gecht, Daniel R Carter, Katleen de Preter, Benjamin Mayer, Lisa Christner, Frank Speleman, Glenn M Marshall, Klaus-Michael Debatin, Christian Beltinger
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 24 Issue 22 Pg. 5772-5783 (11 15 2018) ISSN: 1557-3265 [Electronic] United States
• PMID: 29925504 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• MYCN protein, human
• N-Myc Proto-Oncogene Protein
• Lactic Acid
• L-Lactate Dehydrogenase
• LDHA protein, human
• Glucose

Topics

• Animals
• Cell Line, Tumor
• Disease Models, Animal
• Disease Progression
• Female
• Gene Expression
• Glucose (metabolism)
• Glycolysis
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• L-Lactate Dehydrogenase (genetics, metabolism)
• Lactic Acid (metabolism)
• Mice
• Mice, Knockout
• N-Myc Proto-Oncogene Protein (genetics, metabolism)
• Neuroblastoma (genetics, metabolism, mortality, pathology)
• Prognosis
• Risk Factors
• Survival Analysis