Double-Stranded RNA-dependent Protein Kinase (PKR) of Lung Cancer Cells via Up-Regulation of the ) Induces Apoptosis

Adenoviral-mediated overexpression of the melanoma differentiationassociated gene 7 (Ad-mda7) induces apoptosis in a wide range of cancer cells, although the mechanism is not well understood. We report that Ad-mda7 induces and activates the double-stranded RNA-dependent protein kinase (PKR), which leads to phosphorylation of the subunit of eukaryotic translation initiation factor 2 (eIF-2 ) and the induction of apoptosis in lung cancer cells. Treatment with 2-aminopurine (2-AP), a serine/threonine kinase inhibitor, inhibits PKR activation, eIF2 phosphorylation, and apoptosis induction by Ad-mda7. Additionally, PKR null but not wild-type fibroblasts are resistant to Ad-mda7-induced apoptosis. These results suggest that the activation of PKR and its downstream targets may be a critical pathway for Ad-mda7-mediated apoptosis.