Integrin αvβ3 upregulates integrin-linked kinase expression in human ovarian cancer cells via enhancement of ILK gene transcription

Daniela Lössner, Claudia Abou-Ajram, Anke Benge, Marc Aumercier, Manfred Schmitt, Ute Reuning

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25 Citations (Scopus)

Abstract

We previously showed that integrin aαvbβ3 overexpression and engagement by its ligand vitronectin increased adhesion, motility, and proliferation of human ovarian cancer cells. In search of differentially regulated genes involved in these tumor biological events, we previously identified the integrin-linked kinase (ILK) to be under control of aαvbβ3. In the present investigation we demonstrated significantly upregulated ILK protein as a function of aαvbβ3 in two ovarian cancer cell lines, OV-MZ-6 and OVCAR-3, and proved co-localization at the surface of aαvbβ3-overexpressing cells adherent to vitronectin. Increase of ILK protein was reflected by enhanced ILK promoter activity, an effect, which we further characterized with regard to transcriptional response elements involved. Abrogation of NF-kκB/c-rel or p53 binding augmented ILK promoter activity and preserved induction by aαvbβ3. The AP1-mutant exhibited decreased promoter activity but was also still inducible by aαvbβ3. Disruption of the two DNA consensus motifs for Ets proteins led to divergent observations: mutation of the Ets motif at promoter position -462 bp did not significantly alter promoter activity but still allowed response to aαvbβ3. In contrast, disruption of the second Ets motif at position -85 bp did not only lead to slightly diminished promoter activity but also, in that case, abrogated ILK promoter induction by aαvbβ3. Subsequent co-transfection studies with ets-1 in the presence of the second Ets motif led to additional induction of ILK promoter activity. Taken together, these data suggest that ets-1 binding to the second Ets DNA motif strongly contributes to aαvbβ3-mediated ILK upregulation. By increasing ILK as an important integrin-proximal kinase, aαvbβ3 may promote its intracellular signaling and tumor biological processes arising thereof in favor of ovarian cancer metastasis.

Original languageEnglish
Pages (from-to)367-375
Number of pages9
JournalJournal of Cellular Physiology
Volume220
Issue number2
DOIs
Publication statusPublished - Aug 2009
Externally publishedYes

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