Consequences of blunting the mevalonate pathway in cancer identified by a pluri-omics approach

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.

NMR-based metabolomics and fluxomics: developments and future prospects

“…129,130 In untargeted metabolomics, multiple studies have been showing the complementarity of the MS and NMR to solve specific biological questions. 3,131 But even more promising results arise from the recent development of advanced statistical approaches dedicated to the integration of analytical data from multiple platforms. 132,133 While NMR has a lot to bring to metabolomics and fluxomics, these recent works certainly predict a bright future for multi-technique analytical workflows in the field.…”

MDM2-Dependent Rewiring of Metabolomic and Lipidomic Profiles in Dedifferentiated Liposarcoma Models

“…In previous literature, 3-hydroxy-3-methyl-glutaryl-CoA reductase reductase inhibitor (statin) treatment was noted to result in ceramide elevation [14][15][16]. Given the importance of the ceramide metabolites in our findings, we wanted to explore whether induction of ceramides altered chemosensitivity.…”

Curbing Lipids: Impacts ON Cancer and Viral Infection

“…Statins are competitive inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) and are referred to as cholesterol-lowering drugs as these regulate the rate-limiting step of the cholesterol synthesis pathway [118,119,120]. Statins target the MVA pathway by inhibiting HMGCR and reducing the levels of mevalonate and ultimately reducing plasma cholesterol [121] (Figure 3).…”

“…Statins, therefore, reduce metastatic potentials and improve the survival rates in metastatic breast cancer mouse models [122,123]. Statins induce apoptosis of many cancer cell types and block pathways driving cell division in several types of leukemias and lymphomas [118,119,120]. Furthermore, an inverse correlation between cancer risk and statin use has been shown [124].…”