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DNA Damage and Cellular Stress Responses

Akt1 Activation Can Augment Hypoxia-Inducible Factor-1 Expression by Increasing Protein Translation through a Mammalian Target of Rapamycin–Independent Pathway

¹ Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; ² Department of Radiation Oncology, Emory University School of Medicine, Atlanta, Georgia; and ³ Departments of Radiation Biology and Oncology, Oxford University, Oxford, United Kingdom

Requests for reprints: Amit Maity, Department of Radiation Oncology, University of Pennsylvania School of Medicine, 195 John Morgan Building, 3620 Hamilton Walk, Philadelphia, PA 19104. Phone: 215-614-0078; Fax: 215-898-0090. E-mail: maity{at}xrt.upenn.edu

The phosphoinositide 3-kinase (PI3K)/Akt pathway is commonly activated in cancer; therefore, we investigated its role in hypoxia-inducible factor-1 (HIF-1) 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-1 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-1 induction in response to hypoxia and decreased HIF-1 accumulation in the presence of the proteasomal inhibitor MG132. Akt small interfering RNA (siRNA) also decreased HIF-1 induction under hypoxia and its accumulation in normoxia in the presence of dimethyloxallyl glycine, a prolyl hydroxylase inhibitor that prevents HIF-1 degradation. Metabolic labeling studies showed that Akt siRNA decreased HIF-1 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-1 induction in a variety of cell lines, a finding that was confirmed using mTOR siRNA. Furthermore, neither mTOR siRNA nor rapamycin decreased HIF-1 translation as determined by metabolic labeling studies. Therefore, our results indicate that Akt can augment HIF-1 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-1 expression when cells were cultured in low serum, but this seems to represent a different pathway. (Mol Cancer Res 2006;4(7):471–9)

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