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.
Highlights
Neuroblastoma (NB) is the most common extracranial solid tumor of childhood
High expression of lactate dehydrogenase A (LDHA) is independently associated with outcome of NB, and NB cells can be inhibited by depletion of LDHA or LDHB
As little is known about aerobic glycolysis, LDHA, and LDHB in NB, we investigated these aspects in detail
Summary
Neuroblastoma (NB) is the most common extracranial solid tumor of childhood. The transcription factor MYCN, whose gene is often amplified in poor prognosis NB [1, 2], has long been known to convey a poor prognosis by inducing diverse targetNote: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).Ó2018 American Association for Cancer Research.genes [3]. The transcription factor MYCN, whose gene is often amplified in poor prognosis NB [1, 2], has long been known to convey a poor prognosis by inducing diverse target. Novel prognostic markers and therapeutic targets are needed. Known as the Warburg effect, is a hallmark of cancers, including NB [6,7,8]. As aerobic glycolysis occurs in cancer but not in normal cells, it constitutes a promising therapeutic target. Along this line, inhibition of aerobic glycolysis has been shown to decrease growth of cancer cells, including NB [10,11,12]
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call