Akt1 activation can augment hypoxia-inducible factor-1alpha expression by increasing protein translation through a mammalian target of rapamycin-independent pathway
| Autor: | Nabendu Pore, Eric J. Bernhard, Hui-Kuo G. Shu, Amit Maity, Zibin Jiang, Gary D. Kao |
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| Rok vydání: | 2006 |
| Předmět: |
Male
Vascular Endothelial Growth Factor A Cancer Research Small interfering RNA Morpholines AKT1 Biology Transfection Phosphatidylinositol 3-Kinases Cell Line Tumor PTEN Humans Enzyme Inhibitors RNA Small Interfering Molecular Biology Protein kinase B PI3K/AKT/mTOR pathway Phosphoinositide-3 Kinase Inhibitors TOR Serine-Threonine Kinases RPTOR PTEN Phosphohydrolase Hypoxia-Inducible Factor 1 alpha Subunit Cell biology Enzyme Activation Oncology Hypoxia-inducible factors Chromones Protein Biosynthesis Cancer research biology.protein Glioblastoma Protein Kinases Proto-Oncogene Proteins c-akt |
| Zdroj: | Molecular cancer research : MCR. 4(7) |
| ISSN: | 1541-7786 |
| Popis: | The phosphoinositide 3-kinase (PI3K)/Akt pathway is commonly activated in cancer; therefore, we investigated its role in hypoxia-inducible factor-1α (HIF-1α) regulation. Inhibition of PI3K in U87MG glioblastoma cells, which have activated PI3K/Akt activity secondary to phosphatase and tensin homologue deleted on chromosome 10 (PTEN) mutation, with LY294002 blunted the induction of HIF-1α protein and its targets vascular endothelial growth factor and glut1 mRNA in response to hypoxia. Introduction of wild-type PTEN into these cells also blunted HIF-1α induction in response to hypoxia and decreased HIF-1α accumulation in the presence of the proteasomal inhibitor MG132. Akt small interfering RNA (siRNA) also decreased HIF-1α induction under hypoxia and its accumulation in normoxia in the presence of dimethyloxallyl glycine, a prolyl hydroxylase inhibitor that prevents HIF-1α degradation. Metabolic labeling studies showed that Akt siRNA decreased HIF-1α translation in normoxia in the presence of dimethyloxallyl glycine and in hypoxia. Inhibition of mammalian target of rapamycin (mTOR) with rapamycin (10-100 nmol/L) had no significant effect on HIF-1α induction in a variety of cell lines, a finding that was confirmed using mTOR siRNA. Furthermore, neither mTOR siRNA nor rapamycin decreased HIF-1α translation as determined by metabolic labeling studies. Therefore, our results indicate that Akt can augment HIF-1α expression by increasing its translation under both normoxic and hypoxic conditions; however, the pathway we are investigating seems to be rapamycin insensitive and mTOR independent. These observations, which were made on cells grown in standard tissue culture medium (10% serum), were confirmed in PC3 prostate carcinoma cells. We did find that rapamycin could decrease HIF-1α expression when cells were cultured in low serum, but this seems to represent a different pathway. (Mol Cancer Res 2006;4(7):471–9) |
| Databáze: | OpenAIRE |
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