Consequences of blunting the mevalonate pathway in cancer identified by a pluri-omics approach.
Sophie GoulitquerMikaël CroyalJulie LalandeAnne-Lise RoyerYann GuittonDanielle ArzurStéphanie DurandCatherine Le Jossic-CorcosAlain BouchereauPhilippe PotinSerge AkokaJean-Philippe AntignacMichel KrempfVéronique Ferchaud-RoucherPatrick GiraudeauLaurent CorcosPublished in: Cell death & disease (2018)
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.
Keyphrases
- gene expression
- mass spectrometry
- magnetic resonance
- endothelial cells
- papillary thyroid
- dna methylation
- oxidative stress
- ms ms
- endoplasmic reticulum stress
- squamous cell
- high resolution
- cell cycle arrest
- genome wide
- cell death
- pluripotent stem cells
- amino acid
- high glucose
- induced pluripotent stem cells
- transcription factor
- liquid chromatography
- single cell
- cardiovascular disease
- fatty acid
- type diabetes
- lymph node metastasis
- capillary electrophoresis
- cancer therapy
- rna seq
- contrast enhanced
- low grade
- young adults
- magnetic resonance imaging
- high performance liquid chromatography
- childhood cancer
- tyrosine kinase
- adverse drug
- bioinformatics analysis