GSK3 and PKB/Akt are associated with integrin-mediated regulation of PTHrP, IL-6 and IL-8 expression in FG pancreatic cancer cells.
We have demonstrated recently that PTHrP is upregulated in pancreatic adenocarcinoma and that the ECM exerts regulatory control, at least in part, over PTHrP expression. In our present study, we examined the potential signaling interactions between these 2 pathways. Our results demonstrate that, under serum-free conditions, adhesion of FG pancreatic adenocarcinoma cells on Fn is mediated by the alpha5beta1 integrin, whereas adhesion to Type I collagen is mediated by the alpha2beta1 integrin. alpha5beta1 integrin-mediated adhesion to Fn results in a phenotype that includes a reduction in cell proliferation, increased E-cadherin localization in cell-cell contacts, increased beta-catenin localization throughout the cell, inhibition of haptokinetic cell migration, and increased expression of PTHrP, IL-6 and IL-8 relative to alpha2beta1 integrin-mediated adhesion on Type I collagen. A phosphoprotein immunoblotting screen of FG pancreatic cancer cells grown on either Fn or Type I collagen indicates that GSK3 and PKB/Akt are differentially phosphorylated on these 2 substrates. These results implicate GSK3 and PKB/Akt in the integrin-mediated regulation of PTHrP, IL-6 and IL-8 in pancreatic cancer.
Grzesiak
John J
JJ
Department of Surgery, University of California, San Diego, CA 92161, USA.
Smith
Kathy C
KC
Burton
Douglas W
DW
Deftos
Leonard J
LJ
Bouvet
Michael
M
D000230:Adenocarcinoma / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion; D002465:Cell Movement; D003094:Collagen / Q000737:chemistry / Q000378:metabolism; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D006801:Humans; D038982:Integrin alpha2beta1 / Q000378:metabolism; D039081:Integrin alpha5beta1 / Q000378:metabolism; D016023:Integrins / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D044162:Parathyroid Hormone-Related Protein / Q000378:metabolism; D010641:Phenotype; D010750:Phosphoproteins / Q000737:chemistry; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D011863:Radioimmunoassay; D015398:Signal Transduction; D013997:Time Factors; D015854:Up-Regulation
D015820:Cadherins; D016895:Culture Media, Serum-Free; D038982:Integrin alpha2beta1; D039081:Integrin alpha5beta1; D016023:Integrins; D015850:Interleukin-6; D016209:Interleukin-8; D044162:Parathyroid Hormone-Related Protein; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D003094:Collagen; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3