Analysis of Epithelial-Mesenchymal Transition Metabolism Identifies Possible Cancer Biomarkers Useful in Diverse Genetic Backgrounds

Frontiers in Oncology

Osbaldo Resendis-Antonio¹  Cecilia Zazueta²  Emilio Rojas³  Meztli Matadamas-Guzman⁴ 

[1] Coordinación de la Investigación Científica—Red de Apoyo a la Investigación, UNAM, Mexico City, Mexico;Departamento de Biomedicina Cardiovascular, Instituto Nacional de Cardiología-Ignacio Chávez, Mexico City, Mexico;Department of Genomic Medicine and Environmental Toxicology, Institute of Biomedical Research, UNAM, Mexico City, Mexico;Human Systems Biology Lab, National Institute of Genomic Medicine, Mexico City, Mexico;Programa de Doctorado en Ciencias Biomédicas, UNAM, Mexico City, Mexico;

关键词: metabolism;    EMT;    glutathione;    mathematical model;    biomarker;   

DOI  :  10.3389/fonc.2020.01309

来源: DOAJ

【 摘 要 】

Epithelial-to-mesenchymal transition (EMT) relates to many molecular and cellular alterations that occur when epithelial cells undergo a switch in differentiation generating mesenchymal-like cells with newly acquired migratory and invasive properties. In cancer cells, EMT leads to drug resistance and metastasis. Moreover, differences in genetic backgrounds, even between patients with the same type of cancer, also determine resistance to some treatments. Metabolic rewiring is essential to induce EMT, hence it is important to identify key metabolic elements for this process, which can be later used to treat cancer cells with different genetic backgrounds. Here we used a mathematical modeling approach to determine which are the metabolic reactions altered after induction of EMT, based on metabolomic and transcriptional data of three non-small cell lung cancer (NSCLC) cell lines. The model suggested that the most affected pathways were the Krebs cycle, amino acid metabolism, and glutathione metabolism. However, glutathione metabolism had many alterations either on the metabolic reactions or at the transcriptional level in the three cell lines. We identified Glutamate-cysteine ligase (GCL), a key enzyme of glutathione synthesis, as an important common feature that is dysregulated after EMT. Analyzing survival data of men with lung cancer, we observed that patients with mutations in GCL catalytic subunit (GCLC) or Glutathione peroxidase 1 (GPX1) genes survived less time than people without mutations on these genes. Besides, patients with low expression of ANPEP, GPX3 and GLS genes also survived less time than those with high expression. Hence, we propose that glutathione metabolism and glutathione itself could be good targets to delay or potentially prevent EMT induction in NSCLC cell lines.

【 授权许可】

Unknown