losartan-potassium and Astrocytoma

Hypoxia-inducible factor-1 (HIF-1) regulates the expression of neuroprotective genes such as erythropoietin (EPO). We investigated the mechanism by which zinc, an excitotoxin-like metal, regulates HIF-1 under hypoxic conditions in astrocytes. In hypoxic LN215 cells, HIF-1alpha stabilized and accumulated in the nucleus, resulting in an increase in its DNA-binding activity to the EPO enhancer. Zinc inhibited hypoxia-induced increases in HIF-1 DNA-binding activity and the HIF-1-dependent mRNA expression of EPO. Zinc did not affect hypoxic stabilization of HIF-1alpha. Nuclear migration of HIF-1alpha upon hypoxia was reduced by zinc. Complete blockade of hypoxia-induced assembly of HIF-1alpha-HIF-1beta complex was observed after treatment of zinc. These findings suggest that zinc hampers hypoxia-stimulated HIF-1 activation in astrocytes by inhibiting nuclear HIF-1alpha translocation and subsequently disrupting HIF-1 heterodimerization.

Topics: Antineoplastic Agents; Astrocytoma; Cell Line, Tumor; Cell Nucleus; Dose-Response Relationship, Drug; Drug Interactions; Electrophoretic Mobility Shift Assay; Erythropoietin; Gene Expression Regulation, Neoplastic; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Proline; Protein Transport; Thiocarbamates; Time Factors; Zinc Sulfate

Insulin-like growth factor-1 (IGF-1) and erythropoietin (EPO) are induced in brain cells after brain ischemia and show synergistic neuroprotective effects. In LN215 astrocytoma cells, IGF-1 induced the activation of hypoxia-inducible factor-1, leading to increases in EPO mRNA levels and the secretion of EPO. Interestingly, blocking the potential action of secreted EPO on LN215 cells with EPO antibody, EPO receptor antibody, and soluble EPO receptor significantly suppressed the effect of IGF-1 on the biosynthesis of EPO. Synergistic action between IGF-1 and recombinant human EPO in the astrocytic production of EPO was observed. These data suggest that the IGF-1-EPO production/secretion process initiates a positive feedback loop of EPO biosynthesis in astrocytes, providing a molecular link between the two neuroprotective cytokines.

Topics: Antibodies; Astrocytoma; Autocrine Communication; Blotting, Western; Cell Line, Tumor; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Gene Expression Regulation; Humans; Hypoxia-Inducible Factor 1; Insulin-Like Growth Factor I; Receptors, Erythropoietin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transcriptional Activation

Topics: Antineoplastic Agents; Astrocytoma; Brain Neoplasms; Cell Hypoxia; Cisplatin; Erythropoietin; Humans; Signal Transduction