eIF2α Kinase PKR Modulates the Hypoxic Response by Stat3-Dependent Transcriptional Suppression of HIF-1α

Hypoxia within the tumor microenvironment promotes angiogenesis, metabolic reprogramming, and tumor progression. In addition to activating hypoxia-inducible factor-1 alpha (HIF-1 alpha), cells also respond to hypoxia by globally inhibiting protein synthesis via serine 51 phosphorylation of translation eukaryotic initiation factor 2 alpha (eIF2 alpha). In this study, we investigated potential roles for stress-activated eIF2 alpha kinases in regulation of HIF-1 alpha. Our investigations revealed that the double-stranded RNA-dependent protein kinase R (PKR) plays a significant role in suppressing HIF-1 alpha expression, acting specifically at the level of transcription. HIF-1 alpha transcriptional repression by PKR was sufficient to impair the hypoxia-induced accumulation of HIF-1 alpha and transcriptional induction of HIF-1 alpha-dependent target genes. Inhibition of HIF-1A transcription by PKR was independent of eIF2 alpha phosphorylation but dependent on inhibition of the signal transducer and activator of transcription 3 (Stat3). Furthermore, HIF-1A repression required the T-cell protein tyrosine phosphatase, which acts downstream of PKR, to suppress Stat3. Our findings reveal a novel tumor suppressor function for PKR, which inhibits HIF-1 alpha expression through Stat3 but is independent of eIF2 alpha phosphorylation. Cancer Res; 70(20); 7820-9. (C) 2010 AACR.