Consequences of blunting the mevalonate pathway in cancer identified by a pluriomics approach

Sophie Goulitquer (1, 2) , Mikael Croyal (3) , Julie Lalande (4) , Anne-Lise Royer , Yann Guitton (5) , Danielle Arzur (2) , Stephanie Durand (6) , Catherine Le Jossic-Corcos (1) , Alain Bouchereau (7) , Philippe Potin (8, 9) , Serge Akoka (10) , Jean-Philippe Antignac (5) , Michel Krempf (11) , Veronique Ferchaud-Roucher (12, 13, 14) , Patrick Giraudeau (15) , Laurent Corcos (1)

1 GGB - Génétique, génomique fonctionnelle et biotechnologies (UMR 1078)
2 LUBEM - Laboratoire Universitaire de Biodiversité et Ecologie Microbienne
3 Centres de Recherche en Nutrition Humaine - CRNH - Nutrition périnatale [Nantes]
4 ESPE Nantes - École supérieure du professorat et de l'éducation - Académie de Nantes
5 LABERCA - Laboratoire d'étude des Résidus et Contaminants dans les Aliments
6 UNH - Unité de Nutrition Humaine
7 IGEPP - Institut de Génétique, Environnement et Protection des Plantes
8 SBR - Station biologique de Roscoff = Roscoff Marine Station
9 LBI2M - Laboratoire de Biologie Intégrative des Modèles Marins
10 LAIEM - Laboratoire d'analyse isotopique et électrochimique de metabolismes
11 UNAM - PRES Université Nantes Angers Le Mans
12 CRNH Ouest - Centre de Recherche en Nutrition Humaine Ouest
13 PhAN - Physiopathologie des Adaptations Nutritionnelles
14 UN - Université de Nantes
15 CEISAM - Chimie Et Interdisciplinarité : Synthèse, Analyse, Modélisation

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.

Mots clés: metabolomics and lipidomics alterations

Mots clés: (lovastatin + docetaxel) combination; gastric cancer cells

Domaines: Chimie

Sophie Goulitquer, Mikael Croyal, Julie Lalande, Anne-Lise Royer, Yann Guitton, et al.. Consequences of blunting the mevalonate pathway in cancer identified by a pluriomics approach. Cell Death and Disease, 2018, 9 (7), pp.745. ⟨10.1038/s41419-018-0761-0⟩. ⟨hal-02140936⟩