Type I collagen and divalent cation shifts disrupt cell-cell adhesion, increase migration, and decrease PTHrP, IL-6, and IL-8 expression in pancreatic cancer cells.
BACKGROUND
We have shown in FG pancreatic cancer cells that alpha2beta1 integrin-mediated type I collagen adhesion decreases parathyroid hormone-related protein (PTHrP), interleukin-6 (IL-6), and interleukin-8 (IL-8) expression, decreases the localization of E-cadherin and beta-catenin in cell-cell contacts, increases cell migration, and increases glycogen synthase kinase 3 (GSK3) and protein kinase B (PKB/Akt) phosphorylation states relative to alpha5beta1 integrin-mediated fibronectin (Fn) adhesion.


OBJECTIVE
To extend our observations in FG cells to other pancreatic cancer cell lines, and to determine whether E-cadherin-mediated cell-cell adhesion and its downstream effectors were functionally involved in the ECM-mediated regulation of PTHrP, IL-6, and IL-8.


METHODS
We used standard biochemical techniques to determine ECM-specific differences in E-cadherin and beta-catenin localization, GSK3 and PKB/Akt phosphorylation, haptokinetic cell migration, and cytokine expression in pancreatic cancer cells. We also conducted functional studies using pharmacological inhibitors for GSK3 and PKB/Akt, as well as elevated Mg2+/Ca2+ ratios similar to pancreatic juice, and examined their effects on cytokine expression.


RESULTS
Differences in E-cadherin and beta-catenin localization along with GSK3 and PKB/Akt phosphorylation occur in multiple pancreatic cancer cell lines, resulting in differences in ECM-mediated haptokinesis and cytokine expression that are generally consistent with previous observations in FG cells. Our functional studies also suggest that E-cadherin-mediated cell-cell adhesion and downstream effectors are involved in PTHrP, IL-6, and IL-8 expression.


CONCLUSIONS
These data indicate that alpha2beta1 integrin-mediated type I collagen adhesion disrupts cell-cell adhesion architecture, resulting in increased migration and decreased PTHrP, IL-6, and IL-8 expression in pancreatic cancer cells.
Grzesiak
John J
JJ
Department of Surgery, University of California, San Diego and Veterans Affairs, San Diego Healthcare System, San Diego, CA 92161, USA.
Smith
Kathy C
KC
Chalberg
Cheryl
C
Burton
Douglas W
DW
Deftos
Leonard J
LJ
Bouvet
Michael
M
D000230:Adenocarcinoma / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002448:Cell Adhesion; D024042:Collagen Type I / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D015972:Gene Expression Regulation, Neoplastic; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism*; D008274:Magnesium / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D044162:Parathyroid Hormone-Related Protein / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D015820:Cadherins; D024042:Collagen Type I; D016023:Integrins; D015850:Interleukin-6; D016209:Interleukin-8; D044162:Parathyroid Hormone-Related Protein; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D008274:Magnesium; D002118:Calcium