Phosphorylated Akt/PKB controls cell growth and apoptosis in intraductal papillary-mucinous tumor and invasive ductal adenocarcinoma of the pancreas.
BACKGROUND
Akt/PKB promotes cell proliferation and rescues cells from apoptosis.


OBJECTIVE
To evaluate the role of Akt/PKB, a key molecule in phosphatidylinositol 3-OH kinase (PI3K) signaling, during the development of pancreatic duct neoplasias such as intraductal papillary-mucinous tumor (IPMT) and invasive ductal adenocarcinoma (IDAC) of the pancreas.


RESULTS
In PK-45H pancreatic cancer cells, the growth-inhibitory and apoptosis-inducing effects of LY294002, a PI3K inhibitor, were detected in a concentration-dependent manner, followed by the reduction of phosphorylated Akt levels. Immunohistochemical analyses revealed that frequent overexpression of phosphorylated Akt (Ser473) was detected in 10 (63%) of 16 IPMTs and 14 (70%) of 20 IDACs. It is interesting that the incidence of Akt phosphorylation closely correlated with Ki-67 immunoreactivity and had an inverse association with the number of cases of apoptotic bodies in both IPMT and IDAC. Although there was no good correlation with other clinicopathologic parameters, the two patients with recurrent IPMT had high levels of phosphorylated Akt.


CONCLUSIONS
Our findings suggest that activation of Akt plays an important role during the progression of these pancreatic duct neoplasias at the early stage. Furthermore, inhibition of the PI3K-Akt/PKB pathway may have therapeutic potential in the treatment of pancreatic duct tumors.
Semba
Shuho
S
First Department of Pathology, Yamagata University School of Medicine, Yamagata, Japan. semba@med.kobe-u.ac.jp
Moriya
Toshiyuki
T
Kimura
Wataru
W
Yamakawa
Mitsunori
M
D000230:Adenocarcinoma / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D002288:Adenocarcinoma, Mucinous / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D000368:Aged; D017209:Apoptosis; D021441:Carcinoma, Pancreatic Ductal / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D002291:Carcinoma, Papillary / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D002455:Cell Division; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D051901:Smad4 Protein; D016019:Survival Analysis; D015534:Trans-Activators / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D002867:Chromones; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D051901:Smad4 Protein; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; C497796:SMAD4 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494918:AKT1 protein, human