Cargando…

Genetic and Drug Inhibition of LDH-A: Effects on Murine Gliomas

SIMPLE SUMMARY: Three different murine glioma cell lines were modified to downregulate expression of the murine LDH-A gene using shRNA knockdown (KD) and compared to pharmacologic (GNE-R-140) inhibition of the LDH enzyme complex, and to shRNA scrambled control (NC) cell lines. The effects of shRNA L...

Descripción completa

Detalles Bibliográficos
Autores principales: Maeda, Masatomo, Ko, Myat, Mane, Mayuresh M., Cohen, Ivan J., Shindo, Masahiro, Vemuri, Kiranmayi, Serganova, Inna, Blasberg, Ronald
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9105502/
https://www.ncbi.nlm.nih.gov/pubmed/35565435
http://dx.doi.org/10.3390/cancers14092306
_version_ 1784708056043487232
author Maeda, Masatomo
Ko, Myat
Mane, Mayuresh M.
Cohen, Ivan J.
Shindo, Masahiro
Vemuri, Kiranmayi
Serganova, Inna
Blasberg, Ronald
author_facet Maeda, Masatomo
Ko, Myat
Mane, Mayuresh M.
Cohen, Ivan J.
Shindo, Masahiro
Vemuri, Kiranmayi
Serganova, Inna
Blasberg, Ronald
author_sort Maeda, Masatomo
collection PubMed
description SIMPLE SUMMARY: Three different murine glioma cell lines were modified to downregulate expression of the murine LDH-A gene using shRNA knockdown (KD) and compared to pharmacologic (GNE-R-140) inhibition of the LDH enzyme complex, and to shRNA scrambled control (NC) cell lines. The effects of shRNA LDH-A knockdown and LDH drug-targeted inhibition (GNE-R-140) on tumor-cell metabolism, tumor growth, and animal survival were similar in each of the cell lines. However, an unexpected increase in the aggressiveness was observed in LDH-A KD and GNE-R-140 treated GL261 intracranial gliomas, but not in CT2A and ALTS1C1 i.c. gliomas. Our results show that LDH-A KD and GNE-R-140 treated GL261 cells are better able to metabolize lactate as a primary carbon source through the TCA cycle, and are a net consumer of lactate. These results suggest that inhibition of LDH-A/glycolysis may not be a general strategy to inhibit the i.c. growth of all gliomas, and that metabolic-inhibition treatment strategies need to be carefully assessed, since the inhibition of glycolysis may lead to the unexpected development and activation of alternative metabolic pathways resulting in enhanced tumor-cell survival in a nutrient-limited environment, leading to increased tumor aggressiveness. ABSTRACT: The effects of the LDH-A depletion via shRNA knockdown on three murine glioma cell lines and corresponding intracranial (i.c.) tumors were studied and compared to pharmacologic (GNE-R-140) inhibition of the LDH enzyme complex, and to shRNA scrambled control (NC) cell lines. The effects of genetic-shRNA LDH-A knockdown and LDH drug-targeted inhibition (GNE-R-140) on tumor-cell metabolism, tumor growth, and animal survival were similar. LDH-A KD and GNE-R-140 unexpectedly increased the aggressiveness of GL261 intracranial gliomas, but not CT2A and ALTS1C1 i.c. gliomas. Furthermore, the bioenergetic profiles (ECAR and OCR) of GL261 NC and LDH-A KD cells under different nutrient limitations showed that (a) exogenous pyruvate is not a major carbon source for metabolism through the TCA cycle of native GL261 cells; and (b) the unique upregulation of LDH-B that occurs in GL261 LDH-A KD cells results in these cells being better able to: (i) metabolize lactate as a primary carbon source through the TCA cycle, (ii) be a net consumer of lactate, and (iii) showed a significant increase in the proliferation rate following the addition of 10 mM lactate to the glucose-free media (only seen in GL261 KD cells). Our study suggests that inhibition of LDH-A/glycolysis may not be a general strategy to inhibit the i.c. growth of all gliomas, since the level of LDH-A expression and its interplay with LDH-B can lead to complex metabolic interactions between tumor cells and their environment. Metabolic-inhibition treatment strategies need to be carefully assessed, since the inhibition of glycolysis (e.g., inhibition of LDH-A) may lead to the unexpected development and activation of alternative metabolic pathways (e.g., upregulation of lipid metabolism and fatty-acid oxidation pathways), resulting in enhanced tumor-cell survival in a nutrient-limited environment and leading to increased tumor aggressiveness.
format Online
Article
Text
id pubmed-9105502
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-91055022022-05-14 Genetic and Drug Inhibition of LDH-A: Effects on Murine Gliomas Maeda, Masatomo Ko, Myat Mane, Mayuresh M. Cohen, Ivan J. Shindo, Masahiro Vemuri, Kiranmayi Serganova, Inna Blasberg, Ronald Cancers (Basel) Article SIMPLE SUMMARY: Three different murine glioma cell lines were modified to downregulate expression of the murine LDH-A gene using shRNA knockdown (KD) and compared to pharmacologic (GNE-R-140) inhibition of the LDH enzyme complex, and to shRNA scrambled control (NC) cell lines. The effects of shRNA LDH-A knockdown and LDH drug-targeted inhibition (GNE-R-140) on tumor-cell metabolism, tumor growth, and animal survival were similar in each of the cell lines. However, an unexpected increase in the aggressiveness was observed in LDH-A KD and GNE-R-140 treated GL261 intracranial gliomas, but not in CT2A and ALTS1C1 i.c. gliomas. Our results show that LDH-A KD and GNE-R-140 treated GL261 cells are better able to metabolize lactate as a primary carbon source through the TCA cycle, and are a net consumer of lactate. These results suggest that inhibition of LDH-A/glycolysis may not be a general strategy to inhibit the i.c. growth of all gliomas, and that metabolic-inhibition treatment strategies need to be carefully assessed, since the inhibition of glycolysis may lead to the unexpected development and activation of alternative metabolic pathways resulting in enhanced tumor-cell survival in a nutrient-limited environment, leading to increased tumor aggressiveness. ABSTRACT: The effects of the LDH-A depletion via shRNA knockdown on three murine glioma cell lines and corresponding intracranial (i.c.) tumors were studied and compared to pharmacologic (GNE-R-140) inhibition of the LDH enzyme complex, and to shRNA scrambled control (NC) cell lines. The effects of genetic-shRNA LDH-A knockdown and LDH drug-targeted inhibition (GNE-R-140) on tumor-cell metabolism, tumor growth, and animal survival were similar. LDH-A KD and GNE-R-140 unexpectedly increased the aggressiveness of GL261 intracranial gliomas, but not CT2A and ALTS1C1 i.c. gliomas. Furthermore, the bioenergetic profiles (ECAR and OCR) of GL261 NC and LDH-A KD cells under different nutrient limitations showed that (a) exogenous pyruvate is not a major carbon source for metabolism through the TCA cycle of native GL261 cells; and (b) the unique upregulation of LDH-B that occurs in GL261 LDH-A KD cells results in these cells being better able to: (i) metabolize lactate as a primary carbon source through the TCA cycle, (ii) be a net consumer of lactate, and (iii) showed a significant increase in the proliferation rate following the addition of 10 mM lactate to the glucose-free media (only seen in GL261 KD cells). Our study suggests that inhibition of LDH-A/glycolysis may not be a general strategy to inhibit the i.c. growth of all gliomas, since the level of LDH-A expression and its interplay with LDH-B can lead to complex metabolic interactions between tumor cells and their environment. Metabolic-inhibition treatment strategies need to be carefully assessed, since the inhibition of glycolysis (e.g., inhibition of LDH-A) may lead to the unexpected development and activation of alternative metabolic pathways (e.g., upregulation of lipid metabolism and fatty-acid oxidation pathways), resulting in enhanced tumor-cell survival in a nutrient-limited environment and leading to increased tumor aggressiveness. MDPI 2022-05-06 /pmc/articles/PMC9105502/ /pubmed/35565435 http://dx.doi.org/10.3390/cancers14092306 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Maeda, Masatomo
Ko, Myat
Mane, Mayuresh M.
Cohen, Ivan J.
Shindo, Masahiro
Vemuri, Kiranmayi
Serganova, Inna
Blasberg, Ronald
Genetic and Drug Inhibition of LDH-A: Effects on Murine Gliomas
title Genetic and Drug Inhibition of LDH-A: Effects on Murine Gliomas
title_full Genetic and Drug Inhibition of LDH-A: Effects on Murine Gliomas
title_fullStr Genetic and Drug Inhibition of LDH-A: Effects on Murine Gliomas
title_full_unstemmed Genetic and Drug Inhibition of LDH-A: Effects on Murine Gliomas
title_short Genetic and Drug Inhibition of LDH-A: Effects on Murine Gliomas
title_sort genetic and drug inhibition of ldh-a: effects on murine gliomas
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9105502/
https://www.ncbi.nlm.nih.gov/pubmed/35565435
http://dx.doi.org/10.3390/cancers14092306
work_keys_str_mv AT maedamasatomo geneticanddruginhibitionofldhaeffectsonmurinegliomas
AT komyat geneticanddruginhibitionofldhaeffectsonmurinegliomas
AT manemayureshm geneticanddruginhibitionofldhaeffectsonmurinegliomas
AT cohenivanj geneticanddruginhibitionofldhaeffectsonmurinegliomas
AT shindomasahiro geneticanddruginhibitionofldhaeffectsonmurinegliomas
AT vemurikiranmayi geneticanddruginhibitionofldhaeffectsonmurinegliomas
AT serganovainna geneticanddruginhibitionofldhaeffectsonmurinegliomas
AT blasbergronald geneticanddruginhibitionofldhaeffectsonmurinegliomas