Universität zu Köln

Dorneburg, Carmen, Fischer, Matthias, Barth, Thomas F. E., Mueller-Klieser, Wolfgang, Hero, Barbara, Gecht, Judith, Carter, Daniel R., de Preter, Katleen, Mayer, Benjamin, Christner, Lisa, Speleman, Frank, Marshall, Glenn M., Debatin, Klaus-Michael ORCID: 0000-0002-8397-1886 and Beltinger, Christian (2018). LDHA in Neuroblastoma Is Associated with Poor Outcome and Its Depletion Decreases Neuroblastoma Growth Independent of Aerobic Glycolysis. Clin. Cancer Res., 24 (22). S. 5772 - 5784. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 1557-3265

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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. (C) 2018 AACR.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Dorneburg, Carmen UNSPECIFIED UNSPECIFIED UNSPECIFIED Fischer, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Barth, Thomas F. E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mueller-Klieser, Wolfgang UNSPECIFIED UNSPECIFIED UNSPECIFIED Hero, Barbara UNSPECIFIED UNSPECIFIED UNSPECIFIED Gecht, Judith UNSPECIFIED UNSPECIFIED UNSPECIFIED Carter, Daniel R. UNSPECIFIED UNSPECIFIED UNSPECIFIED de Preter, Katleen UNSPECIFIED UNSPECIFIED UNSPECIFIED Mayer, Benjamin UNSPECIFIED UNSPECIFIED UNSPECIFIED Christner, Lisa UNSPECIFIED UNSPECIFIED UNSPECIFIED Speleman, Frank UNSPECIFIED UNSPECIFIED UNSPECIFIED Marshall, Glenn M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Debatin, Klaus-Michael UNSPECIFIED orcid.org/0000-0002-8397-1886 UNSPECIFIED Beltinger, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-165668
DOI:	10.1158/1078-0432.CCR-17-2578
Journal or Publication Title:	Clin. Cancer Res.
Volume:	24
Number:	22
Page Range:	S. 5772 - 5784
Date:	2018
Publisher:	AMER ASSOC CANCER RESEARCH
Place of Publication:	PHILADELPHIA
ISSN:	1557-3265
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DEHYDROGENASE 5 EXPRESSION; LACTIC-ACID PRODUCTION; LACTATE-DEHYDROGENASE; N-MYC; TUMOR PROGRESSION; CANCER; INHIBITION; METABOLISM; GENE Multiple languages Oncology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/16566