Dataset Information

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

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 ?-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-?, which was confirmed by ?-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.

SUBMITTER: Piva MBR

PROVIDER: S-EPMC5615340 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Publications

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

Piva Maria B R MBR Jakubzig Bastian B Bendas Gerd G

Cancers 20170916 9

<h4>Background</h4>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.<h4>Methods</h4>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 betwee ...[more]

PMID: 28926938

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Project description:Melanoma patients experience inferior survival after biochemotherapy when their tumors contain numerous cells expressing the inducible isoform of NO synthase (iNOS) and elevated levels of nitrotyrosine, a product derived from NO. Although several lines of evidence suggest that NO promotes tumor growth and increases resistance to chemotherapy, it is unclear how it shapes these outcomes. Here we demonstrate that modulation of NO-mediated S-nitrosation of cellular proteins is strongly associated with the pattern of response to the anticancer agent cisplatin in human melanoma cells in vitro. Cells were shown to express iNOS constitutively, and to generate sustained nanomolar levels of NO intracellularly. Inhibition of NO synthesis or scavenging of NO enhanced cisplatin-induced apoptotic cell death. Additionally, pharmacologic agents disrupting S-nitrosation markedly increased cisplatin toxicity, whereas treatments favoring stabilization of S-nitrosothiols (SNOs) decreased its cytotoxic potency. Activity of the proapoptotic enzyme caspase-3 was higher in cells treated with a combination of cisplatin and chemicals that decreased NO/SNOs, whereas lower activity resulted from cisplatin combined with stabilization of SNOs. Constitutive protein S-nitrosation in cells was detected by analysis with biotin switch and reduction/chemiluminescence techniques. Moreover, intracellular NO concentration increased significantly in cells that survived cisplatin treatment, resulting in augmented S-nitrosation of caspase-3 and prolyl-hydroxylase-2, the enzyme responsible for targeting the prosurvival transcription factor hypoxia-inducible factor-1? for proteasomal degradation. Because activities of these enzymes are inhibited by S-nitrosation, our data thus indicate that modulation of intrinsic intracellular NO levels substantially affects cisplatin toxicity in melanoma cells. The underlying mechanisms may thus represent potential targets for adjuvant strategies to improve the efficacy of chemotherapy.

Dataset Information

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

Background

Methods

Results

Conclusion

Publications

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

Similar Datasets

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