Abstract
We have previously shown that the combination of statins and taxanes was a powerful trigger of HGT-1 human gastric cancer cells’ apoptosis1. Importantly, several genes involved in the “Central carbon metabolism pathway in cancer”, as reported in the Kyoto Encyclopedia of Genes and Genomes, were either up- (ACLY, ERBB2, GCK, MYC, PGM, PKFB2, SLC1A5, SLC7A5, SLC16A3,) or down- (IDH, MDH1, OGDH, P53, PDK) regulated in response to the drug association. In the present study, we conducted non-targeted metabolomics and lipidomics analyses by complementary methods and cross-platform initiatives, namely mass spectrometry (GC-MS, LC-MS) and nuclear magnetic resonance (NMR), to analyze the changes resulting from these treatments. We identified several altered biochemical pathways involved in the anabolism and disposition of amino acids, sugars, and lipids. Using the Cytoscape environment with, as an input, the identified biochemical marker changes, we distinguished the functional links between pathways. Finally, looking at the overlap between metabolomics/lipidomics and transcriptome changes, we identified correlations between gene expression modifications and changes in metabolites/lipids. Among the metabolites commonly detected by all types of platforms, glutamine was the most induced (6–7-fold), pointing to an important metabolic adaptation of cancer cells. Taken together, our results demonstrated that combining robust biochemical and molecular approaches was efficient to identify both altered metabolic pathways and overlapping gene expression alterations in human gastric cancer cells engaging into apoptosis following blunting the cholesterol synthesis pathway.
Highlights
Cancer cell metabolism shows strong alterations required for cell activity and growth[2], including a high avidity for glucose and lipids[3,4,5]
In order to evaluate the effects of lovastatin and/or docetaxel on HMG-CoA Red activity, we determined the level of mevalonate produced
Cross-platform principal component analysis In order to see if the treatment of HGT-1 cells by lovastatin and/or docetaxel modified the metabolome and lipidome, we performed Principal Component Analyses (PCA) using, as a first entry, harmonized metabolomics data following Pareto and log[10] transformation to have data from each platform within a similar order of magnitude[13]
Summary
Cancer cell metabolism shows strong alterations required for cell activity and growth[2], including a high avidity for glucose and lipids[3,4,5]. Statins, cholesterollowering drugs used to prevent cardiovascular diseases, are competitive inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA Red) They block mevalonate production, in a rate-limiting step of the Official journal of the Cell Death Differentiation Association. Goulitquer et al Cell Death and Disease (2018)9:745 anticancer taxane compound used to treat breast and gastric cancer[10], promotes microtubules assembly and stabilizes the polymers against depolymerization, thereby inhibiting microtubule dynamics[11]. We reported that both lovastatin and docetaxel triggered efficient apoptosis of HGT-1 human gastric cancer cells, and colon or liver cancer cells[1]. We showed that lovastatin triggered numerous gene expression changes, whereas docetaxel had little effects[1]
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