Metabolic and transcriptional profiling reveals pyruvate dehydrogenase kinase 4 as a mediator of epithelial-mesenchymal transition and drug resistance in tumor cellsReportar como inadecuado




Metabolic and transcriptional profiling reveals pyruvate dehydrogenase kinase 4 as a mediator of epithelial-mesenchymal transition and drug resistance in tumor cells - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Cancer and Metabolism

, 2:20

First Online: 03 November 2014Received: 31 March 2014Accepted: 11 September 2014DOI: 10.1186-2049-3002-2-20

Cite this article as: Sun, Y., Daemen, A., Hatzivassiliou, G. et al. Cancer Metab 2014 2: 20. doi:10.1186-2049-3002-2-20

Abstract

BackgroundAccumulating preclinical and clinical evidence implicates epithelial-mesenchymal transition EMT in acquired resistance to anticancer drugs; however, mechanisms by which the mesenchymal state determines drug resistance remain unknown.

ResultsTo explore a potential role for altered cellular metabolism in EMT and associated drug resistance, we analyzed the metabolome and transcriptome of three lung cancer cell lines that were rendered drug resistant following experimental induction of EMT. This analysis revealed evidence of metabolic rewiring during EMT that diverts glucose to the TCA cycle. Such rewiring was at least partially mediated by the reduced expression of pyruvate dehydrogenase kinase 4 PDK4, which serves as a gatekeeper of the TCA cycle by inactivating pyruvate dehydrogenase PDH. Overexpression of PDK4 partially blocked TGFβ-induced EMT; conversely, PDK4 inhibition via RNAi-mediated knockdown was sufficient to drive EMT and promoted erlotinib resistance in EGFR mutant lung cancer cells. We identified a novel interaction between PDK4 and apoptosis-inducing factor AIF, an inner mitochondrial protein that appears to play a role in mediating this resistance. In addition, analysis of human tumor samples revealed PDK4-low as a predictor of poor prognosis in lung cancer and that PDK4 expression is dramatically downregulated in most tumor types.

ConclusionsTogether, these findings implicate PDK4 as a critical metabolic regulator of EMT and associated drug resistance.

KeywordsTumor metabolism EMT Drug resistance Pyruvate dehydrogenase kinase Electronic supplementary materialThe online version of this article doi:10.1186-2049-3002-2-20 contains supplementary material, which is available to authorized users.

Download fulltext PDF



Autor: Yuting Sun - Anneleen Daemen - Georgia Hatzivassiliou - David Arnott - Catherine Wilson - Guanglei Zhuang - Min Gao - Peter

Fuente: https://link.springer.com/



DESCARGAR PDF




Documentos relacionados