Estrogen Modulates Metabolic Pathway Adaptation to Available Glucose in Breast Cancer Cells
Autor: | Ellis R. Levin, Mahnaz Razandi, Fiona O'Mahony, Ali Pedram, Brian J. Harvey |
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Rok vydání: | 2012 |
Předmět: |
medicine.medical_specialty
Cell Survival Citric Acid Cycle Estrogen receptor Apoptosis Breast Neoplasms Oxidative phosphorylation Mitochondrion Biology Oxidative Phosphorylation Adenosine Triphosphate Endocrinology Cell Line Tumor Internal medicine Tumor Microenvironment medicine Humans Glycolysis Phosphorylation RNA Small Interfering Molecular Biology Cell Proliferation Original Research Estradiol Estrogens Ketone Oxidoreductases General Medicine Pyruvate dehydrogenase complex Mitochondria Up-Regulation Cell biology Citric acid cycle Metabolic pathway Glucose Receptors Estrogen Anaerobic glycolysis MCF-7 Cells Female RNA Interference Reactive Oxygen Species Proto-Oncogene Proteins c-akt Signal Transduction |
Zdroj: | Molecular Endocrinology. 26:2058-2070 |
ISSN: | 1944-9917 0888-8809 |
Popis: | Most cancers use glucose as substrate for aerobic glycolysis in preference to oxidative phosphorylation. However, variable glucose concentrations within the in-vivo tumor microenvironment may necessitate metabolic plasticity. Furthermore, little information exists on a role for estrogen receptors in modulating possible metabolic adaptations in breast cancer cells. Here we find that MCF-7 cells switch between metabolic pathways depending on glucose availability and 17β-estradiol (E(2)) potentiates adaptation. In high glucose conditions E(2) up-regulates glycolysis via enhanced AKT kinase activity and suppresses tricarboxylic acid cycle activity. After a decrease in extracellular glucose, mitochondrial pathways are activated in preference to glycolysis. In this setting, E(2) suppresses glycolysis and rescues cell viability by stimulating the tricarboxylic acid cycle via the up-regulation of pyruvate dehydrogenase (PDH) activity. E(2) also increases ATP in low glucose-cultured cells, and the novel phosphorylation of PDH by AMP kinase is required for these metabolic compensations. Capitalizing on metabolic vulnerability, knockdown of PDH in the low-glucose state strongly potentiates ionizing radiation-induced apoptosis and reverses the cell survival effects of E(2). We propose that lowering glucose substrate and inhibiting PDH may augment adjuvant therapies for estrogen receptor-positive breast cancer. |
Databáze: | OpenAIRE |
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