ArticleCancer genomics & proteomics
Metabolic Response to the Mitochondrial Toxin 1-Methyl-4-phenylpyridinium (MPP+) in LDH-A/B Double-knockout LS174T Colon Cancer Cells.
Article in Cancer genomics & proteomics. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
1 citing paper in PubMed, 1 citations in OpenAlex.
- Glucose and Glutamine Define Independent Activation-Braking Metabolic States in Triple Negative Breast Cancer Cells.Cancer genomics & proteomicsArticle
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Authors and funding
4 authors at 1 institution in 1 country.
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Abstract
BACKGROUND/
aimRapid glycolytic substrate-level phosphorylation (SLP) and accumulation of lactic acid are characteristics of diverse cancers. Recent advances in drug discovery have included the use of glycolytic inhibitors with mitochondrial targeting drugs to attempt to invoke an energy crisis in aggressive metabolically active chemo-resistant cancers. In this work, we examine the consequences of inhibiting mitochondrial oxidative phosphorylation (OXPHOS) with 1-methyl-4-phenylpyridinium (MPP+) in LS14T colon cancer cells containing a genetic double knock out (DKO) of lactic acid dehydrogenase (LDHA and LDHB). MATERIALS AND
methodsSeveral metabolic parameters were evaluated concomitant to whole transcriptomic (WT) mRNA, microRNA, and long intergenic non-coding RNAs using Affymetrix 2.1 human ST arrays.
resultsMPP+ effectively blocked OXPHOS where a compensatory shift toward anaerobic SLP was only observed in the control vector (CV), and not observed in the LDH-A/B DKOs (lacking the ability to produce lactic acid). Despite this, there was an unexpected resilience to MPP+ in the latter in terms of energy, which displayed significantly higher resting baseline respiratory OXPHOS capacity relative to controls. At the transcriptome level, MPP+ invoked 1738 differential expressed genes (DEGs) out of 48,226; LDH-A/B DKO resulted in 855 DEGs while 349 DEGs were found to be overlapping in both groups versus respective controls, including loss of mitochondrial complex I (subunits 3 and 6), cell cycle transcripts and fluctuations in epigenetic chromatin remodeling systems. In terms of energy, the effects of MPP+ in the CV transcripts reflect the funneling of carbon intermediates toward glycolysis. The LDH-A/B DKO transcripts reflect a flow of carbons away from glycolysis toward the production of acetyl-CoA.
conclusionThe findings from this study suggest a metabolic resilience to MPP+ in cancer cells devoid of LDH-A/B, explainable in-part by higher baseline OXPHOS respiratory ATP production, necessitating more toxin to suppress the electron transport chain.
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