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Cancers 2017, 9(9), 125; doi:10.3390/cancers9090125

Integrin Activation Contributes to Lower Cisplatin Sensitivity in MV3 Melanoma Cells by Inducing the Wnt Signalling Pathway

Department of Pharmacy, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany
These authors contributed equally to this work.
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Author to whom correspondence should be addressed.
Academic Editor: Helen M. Sheldrake
Received: 28 July 2017 / Revised: 12 September 2017 / Accepted: 13 September 2017 / Published: 16 September 2017
(This article belongs to the Special Issue Integrins in Cancer)
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Abstract

Background: integrins have been associated with the development of chemotherapy resistant tumour cells, mostly those of hematopoietic origin, by mediating the binding to the extracellular matrix. The relevance for solid tumour cells and the underlying mechanisms remain elusive. Methods: using MTT assays, we detected the loss in cisplatin sensitivity of human MV3 melanoma cells upon integrin activation. Underlying cellular pathways were evaluated by flow cytometry. A crosstalk between integrin activation and the canonical wnt signalling pathway was tested by measuring β-catenin activity. Results: MV3 cells display a higher resistance against cisplatin cytotoxicity when cellular integrins were activated by manganese or collagen. Proteome profiler array showed a deregulation of the integrin expression pattern by cisplatin. Integrin activation by manganese induces the phosphorylation of PI3K/AKT. The inhibition of PI3K using BEZ235 strongly increases cell sensitivity to cisplatin, blocking manganese and collagen effects. PI3K/AKT activates wnt signalling by blocking Gsk3-β, which was confirmed by β-catenin up-regulation and nuclear localization. Integrins did not affect E-cadherin expression levels, thus endothelial to mesenchymal transition (EMT) can be excluded. Conclusion: This is the first report on an integrin/wnt signalling activation axis addressing the consequences for chemotherapy sensitiveness of melanoma cells, which thus offers novel therapeutic targets for approaches to interfere with chemoresistance. View Full-Text
Keywords: chemoresistance; cisplatin; integrin; melanoma; PI3K/AKT; wnt pathway chemoresistance; cisplatin; integrin; melanoma; PI3K/AKT; wnt pathway
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Piva, M.B.R.; Jakubzig, B.; Bendas, G. Integrin Activation Contributes to Lower Cisplatin Sensitivity in MV3 Melanoma Cells by Inducing the Wnt Signalling Pathway. Cancers 2017, 9, 125.

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