title: Lysophosphatidic Acid disrupts junctional integrity and epithelial cohesion in ovarian cancer cells.
abstract: Ovarian cancer metastasizes via exfoliation of free-floating cells and multicellular aggregates from the primary tumor to the peritoneal cavity. A key event in EOC metastasis is disruption of cell-cell contacts via modulation of intercellular junctional components including cadherins. Ascites is rich in lysophosphatidic acid (LPA), a bioactive lipid that may promote early events in ovarian cancer dissemination. The objective of this paper was to assess the effect of LPA on E-cadherin junctional integrity. We report a loss of junctional E-cadherin in OVCAR3, OVCA429, and OVCA433 cells exposed to LPA. LPA-induced loss of E-cadherin was concentration and time dependent. LPA increased MMP-9 expression and promoted MMP-9-catalyzed E-cadherin ectodomain shedding. Blocking LPA receptor signaling inhibited MMP-9 expression and restored junctional E-cadherin staining. LPA-treated cells demonstrated a significant decrease in epithelial cohesion. Together these data support a model wherein LPA induces MMP-9 expression and MMP-9-catalyzed E-cadherin ectodomain shedding, resulting in loss of E-cadherin junctional integrity and epithelial cohesion, facilitating metastatic dissemination of ovarian cancer cells.
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, 1234 Notre Dame Avenue, A200D Harper Hall, Notre Dame, IN 46557, USA.
authors.forename: Yueying
authors.initials: Y
authors.lastname: Liu
authors.forename: Rebecca
authors.initials: R
authors.lastname: Burkhalter
authors.forename: Jaime
authors.initials: J
authors.lastname: Symowicz
authors.forename: Kim
authors.initials: K
authors.lastname: Chaffin
authors.forename: Shawn
authors.initials: S
authors.lastname: Ellerbroek
authors.forename: M Sharon
authors.initials: MS
authors.lastname: Stack