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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

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Abstract

Background: We have shown in FG pancreatic cancer cells that α2β1 integrin-mediated type I collagen adhesion decreases parathyroid hormone-related protein (PTHrP), inerleukin-6 (IL-6), and interleukin-8 (IL-8) expression, decreases the localization of E-cadherin and β-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 α5β1 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 β-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 β-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 α2β1 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.

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Authors and Affiliations

  1. Department of Surgery (Mail Code-112-E), University of California, Veterans Affairs San Diego Healthcare System, 3350 La Jolla Village Drive, 92161, San Diego, CA

    John J. Grzesiak & Michael Bouvet MD

  2. Department of Medicine (Endocrinology), University of California, San Diego and Veterans Affairs, San Diego Healthcare System, 92161, San Diego, CA

    Kathy C. Smith, Cheryl Chalberg, Douglas W. Burton & Leonard J. Deftos

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  1. John J. Grzesiak
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  2. Kathy C. Smith
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  3. Cheryl Chalberg
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  4. Douglas W. Burton
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  5. Leonard J. Deftos
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  6. Michael Bouvet MD
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Correspondence to Michael Bouvet MD.

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Grzesiak, J.J., Smith, K.C., Chalberg, C. et al. 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. Int J Gastrointest Canc 36, 131–146 (2005). https://doi.org/10.1385/IJGC:36:3:131

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