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

Autor:	Dorneburg C; Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany., Fischer M; Department of Pediatric Oncology and Hematology, Children's Hospital, University of Cologne, Albertus-Magnus-Platz, Köln, Germany., Barth TFE; Institute of Pathology, University Medical Center Ulm, Ulm, Germany., Mueller-Klieser W; Institute of Pathophysiology, University Mainz, Germany., Hero B; Department of Pediatric Oncology and Hematology, Children's Hospital, University of Cologne, Albertus-Magnus-Platz, Köln, Germany., Gecht J; Department of Pediatric Oncology and Hematology, Children's Hospital, University of Cologne, Albertus-Magnus-Platz, Köln, Germany., Carter DR; Children's Cancer Institute Australia, Lowy Cancer Centre, University of New South Wales, NSW, Sydney, Australia., de Preter K; Center for Medical Genetics (CMGG), Ghent University, Ghent, Belgium., Mayer B; Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany., Christner L; Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany., Speleman F; Center for Medical Genetics (CMGG), Ghent University, Ghent, Belgium., Marshall GM; Children's Cancer Institute Australia, Lowy Cancer Centre, University of New South Wales, NSW, Sydney, Australia.; Kids Cancer Centre, Sydney Children's Hospital, Sydney, Australia., Debatin KM; Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany., Beltinger C; Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany. christian.beltinger@uniklinik-ulm.de.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2018 Nov 15; Vol. 24 (22), pp. 5772-5783. Date of Electronic Publication: 2018 Jun 20.
DOI:	10.1158/1078-0432.CCR-17-2578
Abstrakt:	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 . (©2018 American Association for Cancer Research.)
Databáze:	MEDLINE
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