The activation of lactate dehydrogenase induced by mTOR drives neoplastic change in breast epithelial cells
| Autor: | Marzia Govoni, Giuseppina Di Stefano, Marcella Manerba, Antonietta Comparone, Lorenza Di Ianni |
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| Přispěvatelé: | Manerba M, Di Ianni L, Govoni M, Comparone A, Di Stefano G. |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Metabolic Processes Carcinogenesis Cell Enzyme Metabolism lcsh:Medicine medicine.disease_cause Biochemistry chemistry.chemical_compound Endocrinology Glucose Metabolism Breast Tumors Medicine and Health Sciences Insulin Phosphorylation lcsh:Science Enzyme Chemistry Multidisciplinary Kinase TOR Serine-Threonine Kinases Mitochondria Gene Expression Regulation Neoplastic Isoenzymes medicine.anatomical_structure Oncology Cell Processes MCF-7 Cells Carbohydrate Metabolism Female Biological Cultures Glycolysis Research Article Cell Physiology Breast Neoplasms Research and Analysis Methods 03 medical and health sciences Biological Sciences (all) Lactate dehydrogenase Breast Cancer medicine Humans Kinase activity Clonogenic assay PI3K/AKT/mTOR pathway Cell Proliferation Diabetic Endocrinology Biochemistry Genetics and Molecular Biology (all) L-Lactate Dehydrogenase lcsh:R Biology and Life Sciences Cancers and Neoplasms Epithelial Cells Cell Biology Cell Cultures Hormones Cell Metabolism 030104 developmental biology Metabolism chemistry Cancer cell Cancer research Enzymology lcsh:Q Lactate Dehydrogenase 5 |
| Zdroj: | PLoS ONE PLoS ONE, Vol 13, Iss 8, p e0202588 (2018) |
| ISSN: | 1932-6203 |
| Popis: | mTOR kinase and the A isoform of lactate dehydrogenase (LDH-A) are key players controlling the metabolic characteristics of cancer cells. By using cultured human breast cells as a “metabolic tumor” model, we attempted to explore the correlation between these two factors. “Metabolic tumors” are defined as neoplastic conditions frequently associated with features of the metabolic syndrome, such as hyper-insulinemia and hyper-glycemia. MCF-7 cells (a well differentiated carcinoma) and MCF-10A cells (a widely used model for studying normal breast cell transformation) were used in this study. These cells were exposed to known factors triggering mTOR activation. In both treated cultures, we evaluated the link between mTOR kinase activity and the level of LDH expression / function. Furthermore, we elaborated the metabolic changes produced in cells by the mTOR-directed LDH-A up-regulation. Interestingly, we observed that in the non-neoplastic MCF-10A culture, mTOR-directed up-regulation of LDH-A was followed by a reprogramming of cell metabolism, which showed an increased dependence on glycolysis rather than on oxidative reactions. As a consequence, lactate production appeared to be enhanced and cells began to display increased self-renewal and clonogenic power: signals suggestive of neoplastic change. Enhanced clono-genicity of cells was abolished by rapamycin treatment, and furthermore heavily reduced by LDH enzymatic inhibition. These results highlighted a mechanistic link between metabolic alterations and tumorigenesis, whereby suggesting LDH inhibition as a possible chemo-preventive measure to target the metabolic alterations driving neoplastic change. |
| Databáze: | OpenAIRE |
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