title: Estrogen modulates metabolic pathway adaptation to available glucose in breast cancer cells.
abstract: 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.
authors.affiliation: Division of Endocrinology, Department of Veterans Affairs Medical Center, Long Beach, California 90822, USA.
authors.forename: Fiona
authors.initials: F
authors.lastname: O'Mahony
authors.forename: Mahnaz
authors.initials: M
authors.lastname: Razandi
authors.forename: Ali
authors.initials: A
authors.lastname: Pedram
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Harvey
authors.forename: Ellis R
authors.initials: ER
authors.lastname: Levin
mesh_terms: D000255:Adenosine Triphosphate; D017209:Apoptosis / Q000528:radiation effects; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D002952:Citric Acid Cycle; D004958:Estradiol / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis / Q000235:genetics*; D006801:Humans; D007658:Ketone Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D061986:MCF-7 Cells; D008928:Mitochondria / Q000378:metabolism; D010085:Oxidative Phosphorylation; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D059016:Tumor Microenvironment; D015854:Up-Regulation
chemical_list: D004967:Estrogens; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D011960:Receptors, Estrogen; D004958:Estradiol; D000255:Adenosine Triphosphate; D007658:Ketone Oxidoreductases; C053164:pyruvate dehydrogenase (NADP+); D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose