Genetic and drug inhibition of LDH-A: Effects on murine gliomas Journal Article
| Authors: | Maeda, M.; Ko, M.; Mane, M. M.; Cohen, I. J.; Shindo, M.; Vemuri, K.; Serganova, I.; Blasberg, R. |
| Article Title: | Genetic and drug inhibition of LDH-A: Effects on murine gliomas |
| 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 sug-gests 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. © 2022 by the authors. Licensee MDPI, Basel, Switzerland. |
| Keywords: | glioblastoma; tumor growth; lactate; gne-r-140; immunocompetent host animals; ldh isoenzymes; ldh-a and ldh-b immunohistochemistry; ldh-a shrna knockdown; rna se-qence analyses |
| Journal Title: | Cancers |
| Volume: | 14 |
| Issue: | 9 |
| ISSN: | 2072-6694 |
| Publisher: | MDPI |
| Date Published: | 2022-05-01 |
| Start Page: | 2306 |
| Language: | English |
| DOI: | 10.3390/cancers14092306 |
| PROVIDER: | scopus |
| PMCID: | PMC9105502 |
| PUBMED: | 35565435 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 June 2022 -- Source: Scopus |
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