Adenoviral transfer of the melanoma differentiation-associated gene 7 (mda7) induces apoptosis of lung cancer cells via up-regulation of the double-stranded RNA-dependent protein kinase (PKR).
Adenoviral-mediated overexpression of the melanoma differentiation-associated gene 7 (Ad-mda7) induces apoptosis in a wide range of cancer cells, although themechanism is not well understood. We report that Ad-mda7 induces andactivates the double-stranded RNA-dependent protein kinase (PKR), which leads to phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF-2alpha) and the induction of apoptosis in lung cancer cells. Treatment with 2-aminopurine (2-AP), a serine/threonine kinase inhibitor, inhibits PKR activation, eIF2alpha 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.
Pataer
Abujiang
A
Department of Thoracic and Cardiovascular Surgery, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Vorburger
Stephan A
SA
Barber
Glen N
GN
Chada
Sunil
S
Mhashilkar
Abner M
AM
Zou-Yang
Helena
H
Stewart
Alexis L
AL
Balachandran
Siddharth
S
Roth
Jack A
JA
Hunt
Kelly K
KK
Swisher
Stephen G
SG
D015075:2-Aminopurine / Q000494:pharmacology; D000256:Adenoviridae / Q000235:genetics; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018014:Gene Transfer Techniques; D016147:Genes, Tumor Suppressor; D006133:Growth Substances / Q000235:genetics*; D006801:Humans; D007378:Interleukins; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D010766:Phosphorylation; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D000099180:Interleukin-24
D015075:2-Aminopurine; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D006133:Growth Substances; D007378:Interleukins; D014157:Transcription Factors; D019892:eIF-2 Kinase; D000099180:Interleukin-24