Insulin/protein kinase B signalling pathway upregulates metastasis-related phenotypes and molecules in H7721 human hepatocarcinoma cell line.
The effect of insulin on cancer metastatic potential was studied in a human hepatocarcinoma cell line, H7721. Cell adhesion to human umbilical vein endothelial cells (HUVECs) and laminin as well as chemotactic cell migration and invasion were selected as the indices of metastasis-related phenotypes for assessment of metastatic potential ex vivo. The results indicated that insulin enhanced all of these metastasis-related phenotypes. After the cells were treated with specific inhibitor of PI3K (LY294002) or transfected with antisense cDNA of PKB (AS-PKB), all of the above phenotypes were attenuated, and they could not be significantly stimulated by insulin, indicating that the insulin effect on metastatic potential was mediated by PI3K and PKB. Only the monoclonal antibody to the sialyl Lewis X (SLe(x)), but not antibodies to other Lewis antigens, significantly blocked the cell adhesion to HUVECs, cell migration and invasion, suggesting that SLe(x) played a crucial role in the metastatic potential of H7721 cells. The upregulation of cell surface SLe(x) and alpha-1,3-fucosyltransferase-VII (alpha-1,3 Fuc T-VII, enzyme for SLe(x) synthesis) was also mediated by PI3K and PKB, since LY294002 and AS-PKB also reduced the expressions of SLe(x) and alpha-1,3 FucT-VII, and attenuated the response to insulin. Furthermore, the alterations in the expressions of PKB protein and activity were correlated to the changes of metastatic phenotypes and SLe(x) expression. Taken together, the insulin/PKB signalling pathway participated in the enhancement of metastatic potential of H7721 cells, which was mediated by the upregulation of the expression of SLe(x) and alpha-1,3 FucT-VII.
Qi
Hui-Ling
HL
Department of Biochemistry, Shanghai Medical College of Fu-Dan University, Shanghai, China.
Zhang
Ying
Y
Ma
Jun
J
Guo
Peng
P
Zhang
Xia-Ying
XY
Chen
Hui-Li
HL
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000235:genetics* / Q000276:immunology / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D018076:DNA, Complementary / Q000235:genetics / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005647:Fucosyltransferases / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D007797:Laminin / Q000378:metabolism; D008113:Liver Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000276:immunology / Q000473:pathology*; D009025:Morpholines / Q000494:pharmacology; D009362:Neoplasm Metastasis; D009844:Oligosaccharides / Q000378:metabolism / Q000502:physiology*; D010641:Phenotype; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D000080506:Sialyl Lewis X Antigen; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D000911:Antibodies, Monoclonal; D002867:Chromones; D018076:DNA, Complementary; D007328:Insulin; D007797:Laminin; D009025:Morpholines; D009844:Oligosaccharides; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D000080506:Sialyl Lewis X Antigen; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D005647:Fucosyltransferases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt