Frequent activation of AKT2 kinase in human pancreatic carcinomas.
Activation of AKT/protein kinase B promotes a variety of biological activities important in tumorigenesis, such as cell survival and cell cycle progression. We previously demonstrated amplification and overexpression of the AKT2 gene in a subset of human pancreatic carcinomas. In this investigation, we assessed AKT2 catalytic activity in 50 frozen pancreatic tissues (37 carcinomas, four benign tumors and nine normal pancreata) by in vitro kinase assay. Twelve of 37 (32%) pancreatic carcinomas showed markedly elevated levels of AKT2 activity compared to normal pancreata and begin pancreatic tumors. To delineate mechanisms contributing to AKT2 activation in malignant pancreatic tumors, we examined the status of upstream components of the phosphatilydlinositol 3-kinase (PI3K)/AKT pathway. Western blot analysis revealed loss of PTEN protein expression in two of the 12 pancreatic carcinomas with activated AKT2. In vitro PI3K assays demonstrated high levels of PI3K activity in seven carcinoma specimens that showed AKT2 activation. Immunohistochemical staining confirmed high levels of phosphorylated (active) AKT in malignant pancreatic tumors compared to normal pancreata. Overall, these data suggest that upstream perturbations of the PI3K/AKT pathway contribute to frequent activation of AKT2 in pancreatic cancer, which may contribute to the pathogenesis of this highly aggressive form of human malignancy.
Altomare
Deborah A
DA
Human Genetic Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
Tanno
Satoshi
S
De Rienzo
Assunta
A
Klein-Szanto
Andres J
AJ
Tanno
Sachie
S
Skele
Kristine L
KL
Hoffman
John P
JP
Testa
Joseph R
JR
D000230:Adenocarcinoma / Q000201:enzymology*; D015153:Blotting, Western; D021441:Carcinoma, Pancreatic Ductal / Q000201:enzymology; D003537:Cystadenoma / Q000201:enzymology; D004789:Enzyme Activation; D006801:Humans; D007150:Immunohistochemistry; D051059:PTEN Phosphohydrolase; D010179:Pancreas / Q000201:enzymology; D010190:Pancreatic Neoplasms / Q000201:enzymology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000276:immunology / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000276:immunology / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D025521:Tumor Suppressor Proteins; C494918:AKT1 protein, human; C494921:AKT2 protein, human; C494929:PTEN protein, human