Significance of Akt phosphorylation on tumor growth and vascular endothelial growth factor expression in human gastric carcinoma.
OBJECTIVE
Hypoxia is known to be a prevalent stress stimulus and increases the transcription of vascular endothelial growth factor (VEGF) mediated by hypoxia inducible factor-1alpha (HIF-1alpha). We investigated the role of phosphatidyl inositol-3 OH kinase (PI3K)-Akt signaling in the regulation of HIF-1alpha and VEGF expression in human gastric adenocarcinoma.


METHODS
The growth-inhibitory and apoptosis-inducing effects of the LY294002 PI3K inhibitor were analyzed in four gastric cancer cell lines and in vivo. The regulatory mechanism of VEGF and HIF-1alpha expression under hypoxic conditions was examined in the cell cultures. In 88 gastric cancer tissue samples, phosphorylated Akt and VEGF expression were analyzed immunohistochemically.


RESULTS
LY294002 suppressed cell proliferation but induced apoptosis with decreased levels of phosphorylated Akt. HIF-1alpha expression and VEGF secretion were induced under hypoxic conditions and VEGF protein secretion was significantly decreased by treatment with LY294002. In tumor samples, phosphorylated Akt expression was detected in 57% of the tumors, which was correlated with high VEGF expression, angiogenesis, clinicopathological parameters as well as a poor outcome.


CONCLUSIONS
These findings suggest that phosphorylated Akt (Ser473) reflects the grade of malignancy in human gastric adenocarcinomas, not only in terms of tumor growth but also with respect to tumor angiogenesis.
Kobayashi
Iwao
I
Division of Surgical Pathology, Department of Biomedical Informatics, Kobe University Graduate School of Medicine, Japan.
Semba
Shuho
S
Matsuda
Yoshiko
Y
Kuroda
Yoshikazu
Y
Yokozaki
Hiroshi
H
D000230:Adenocarcinoma / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D018952:Antigens, CD34 / Q000096:biosynthesis; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D014408:Biomarkers, Tumor / Q000032:analysis; D015153:Blotting, Western; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D004277:DNA, Single-Stranded; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000096:biosynthesis; D051379:Mice; D008819:Mice, Nude; D009025:Morpholines / Q000494:pharmacology; D009368:Neoplasm Transplantation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D016019:Survival Analysis; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000187:drug effects
D018952:Antigens, CD34; D014408:Biomarkers, Tumor; D002867:Chromones; D004277:DNA, Single-Stranded; D004791:Enzyme Inhibitors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019394:Ki-67 Antigen; D009025:Morpholines; D042461:Vascular Endothelial Growth Factor A; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt