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.

Abstract

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.

AIM OF THE STUDY:

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.

• Authors: John J Grzesiak, Kathy C Smith, Cheryl Chalberg, Douglas W Burton, Leonard J Deftos, Michael Bouvet
• Journal: International journal of gastrointestinal cancer (Int J Gastrointest Cancer) Vol. 36 Issue 3 Pg. 131-46 ( 2005) ISSN: 1537-3649 [Print] United States
• PMID: 16720909 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Cadherins
• Collagen Type I
• Integrins
• Interleukin-6
• Interleukin-8
• Parathyroid Hormone-Related Protein
• AKT1 protein, human
• Proto-Oncogene Proteins c-akt
• Glycogen Synthase Kinase 3
• Magnesium
• Calcium

Topics

• Adenocarcinoma (metabolism)
• Cadherins (metabolism)
• Calcium (metabolism)
• Cell Adhesion
• Collagen Type I (metabolism)
• Enzyme-Linked Immunosorbent Assay
• Gene Expression Regulation, Neoplastic
• Glycogen Synthase Kinase 3 (metabolism)
• Humans
• Integrins (metabolism)
• Interleukin-6 (metabolism)
• Interleukin-8 (metabolism)
• Magnesium (metabolism)
• Microscopy, Fluorescence
• Pancreatic Neoplasms (metabolism)
• Parathyroid Hormone-Related Protein (metabolism)
• Phosphorylation
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction
• Tumor Cells, Cultured