Long-Chain Acyl Coenzyme A Dehydrogenase, a Key Player in Metabolic Rewiring/Invasiveness in Experimental Tumors and Human Mesothelioma Cell Lines

Our plain-English summary of Long-Chain Acyl Coenzyme A Dehydrogenase, a Key Player in Metabolic Rewiring/Invasiveness in Experimental Tumors and Human Mesothelioma Cell Lines, by D.L. Pouliquen, G. Ortone, L. Rumiano, et al (Cancers, 2023).

The study

• Authors: D.L. Pouliquen, G. Ortone, L. Rumiano, A. Boissard, C. Henry, S. Blandin, C. Guette, C. Riganti, J. Kopecka
• Journal: Cancers
• Published: 2023;15(11)
• Cited by: 4 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Cross-species investigations of cancer invasiveness are a new approach that has already identified new biomarkers which are potentially useful for improving tumor diagnosis and prognosis in clinical medicine and veterinary science. In this study, we combined proteomic analysis of four experimental rat malignant mesothelioma (MM) tumors with analysis of ten patient-derived cell lines to identify common features associated with mitochondrial proteome rewiring. A comparison of significant abundance changes between invasive and non-invasive rat tumors gave a list of 433 proteins, including 26 proteins reported to be exclusively located in mitochondria. Next, we analyzed the differential expression of genes encoding the mitochondrial proteins of interest in five primary epithelioid and five primary sarcomatoid human MM cell lines; the most impressive increase was observed in the expression of the long-chain acyl coenzyme A dehydrogenase (ACADL). To evaluate the role of this enzyme in migration/invasiveness, two epithelioid and two sarcomatoid human MM cell lines derived from patients with the highest and lowest overall survival were studied. Interestingly, sarcomatoid vs. epithelioid cell lines were characterized by higher migration and fatty oxidation rates, in agreement with ACADL findings. These results suggest that evaluating mitochondrial proteins in MM specimens might identify tumors with higher invasiveness. Data are available via ProteomeXchange with the dataset identifier PXD042942.

In plain English

This was a laboratory study of mitochondrial proteins (proteins in the cell's energy-producing parts) in malignant mesothelioma. It did not analyze asbestos exposure. The authors examined four experimental mesothelioma tumors grown in Fisher F344 rats by injecting tumor cells into the abdomen. The tumors ranged from non-invasive to deeply invasive. When the three invasive tumors were compared with the non-invasive one, 433 proteins differed significantly in amount. Twenty-six of these were reported to be located only in mitochondria. One enzyme, long-chain acyl coenzyme A dehydrogenase (ACADL), increased significantly in each invasive tumor. Tissue staining for ACADL was strongest in the deeply invasive tumor. The authors then studied ten human mesothelioma cell lines, five epithelioid and five sarcomatoid. ACADL showed the largest increase in gene expression in the sarcomatoid lines. In four selected lines, the sarcomatoid cells migrated faster than the epithelioid cells. They also burned more fat for energy (fatty acid oxidation) and produced more ATP, the cell's energy molecule. The drug etomoxir reduced both migration and fatty acid oxidation. The authors concluded that evaluating mitochondrial proteins in mesothelioma specimens might help identify more invasive tumors.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study: protein analysis (proteomics) and tissue staining of experimental rat mesothelioma tumors, plus gene, protein, metabolic and cell-migration experiments on human primary mesothelioma cell lines
• Who was studied: Four experimental mesothelioma tumors in Fisher F344 rats, at increasing stages of invasiveness: non-invasive M5-T2, mildly invasive F4-T2, moderately invasive F5-T1 and deeply invasive M5-T1. The tumors were produced by injecting tumor cells into the abdomen of rats at Nantes, France, between 2011 and 2015. Also ten primary human malignant mesothelioma cell lines (5 epithelioid, 5 sarcomatoid) obtained during diagnostic thoracoscopies, from a hospital biobank in Alessandria, Italy. Four of these (epithelioid UP1 and UP2, sarcomatoid UP6 and UP7) were used for further experiments.
• Exposure: No asbestos exposure was studied. The comparisons were between invasive and non-invasive rat tumors, and between sarcomatoid and epithelioid human cell lines. Some cells were treated with 10 µM of etomoxir, a drug that blocks fatty acid oxidation. The patient table lists asbestos exposure as 'Yes' or 'Unknown' for each patient, but this was not analyzed.
• Main results:
  • Comparing the three invasive rat tumors with the non-invasive rat tumor, 433 proteins differed in abundance with p less than 0.05
  • Of these proteins, 26 were reported to be located exclusively in mitochondria
  • In the rat tumors, ACADL increased significantly in each individual invasive tumor compared with the non-invasive tumor
  • In rat tumor tissue staining, ACADL was absent in the non-invasive tumor, weak in the mildly and moderately invasive tumors, and strong in the deeply invasive M5-T1 tumor
  • In the ten human cell lines, ACADL showed the largest increase in gene expression in sarcomatoid compared with epithelioid lines
  • In the four selected human cell lines, the sarcomatoid lines had higher ACADL mRNA and protein and higher fatty acid oxidation than the epithelioid lines
  • The sarcomatoid human cell lines had more active mitochondrial respiratory complexes and produced more ATP than the epithelioid lines
  • In the human cell lines, etomoxir inhibited cell migration in a scratch assay
  • In the sarcomatoid human cell lines, etomoxir inhibited fatty acid oxidation but did not change ACADL expression
• The authors' conclusion: The authors concluded that ACADL and ATP synthase subunits are highly expressed in invasive rat mesotheliomas and in more aggressive human sarcomatoid mesothelioma cells. They suggested that evaluating mitochondrial proteins in mesothelioma specimens might help identify tumors with higher invasiveness and new potential treatment targets.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Biomarker, Prognosis, Epithelioid, Sarcomatoid, Overall Survival.

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