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Elastin-derived peptides increase invasive capacities of lung cancer cells by post-transcriptional regulation of MMP-2 and uPA

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Abstract

Elastin-rich lung extracellular matrix is largely remodeled during tumor invasion. Elastin degradation produces peptides displaying a wide range of biological activities. These elastin derived peptides (EP) interact with the elastin receptor complex (ERC) but also bind to αVβ3 integrin and galectin-3. In this study, we explored the role of EP and their receptors in tumor progression of lung carcinomas. Non-invasive and invasive lung tumor cell lines were incubated in presence of kappa-elastin (κE) or with synthetic peptides displaying receptor-specific sequences (VGVAPG, GRKRK, AGVPGLGVG and AGVPGFGAG). Modified Boyden chamber assays revealed an increased invasive capacity of invasive cells induced by κE. EP treatment had no effect on cell proliferation but zymography analysis revealed an increase of pro-MMP-2 and uPA levels in the conditioned media of treated cells. Moreover, the active form of MMP-2 was increased in invasive cells. Interestingly, this regulation was not observed at the mRNA level and actinomycin D was unable to inhibit κE effects. We also observed that the regulation of proteases protein level following κE treatment was an early process detectable after 1 h. All these effects could not be inhibited by lactose and V14, two ERC antagonists, or by blocking antibodies against αVβ3 integrin and galectin-3. Finally, VGVAPG and GRKRK failed to reproduce κE effects whereas nonapeptides partially mimicked them. These results demonstrate that treatment with EP up-regulates invasiveness of lung tumor cells via the release of proteolytic enzymes. This modulation involves post-transcriptional mechanisms and a nonapeptide-receptor different from the ERC, αVβ3 integrin and galectin-3.

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Abbreviations

ACTD:

Actinomycin D

AGVPGFGAG:

Ala-Gly-Val-Pro-Gly-Phe-Gly-Ala-Gly

AGVPGLGVG:

Ala-Gly-Val-Pro-Gly-Leu-Gly-Val-Gly

CD:

Circular dichroism

EBP:

Elastin binding protein

ECM:

Extracellular matrix

EDTA:

Ethylenediaminetetraacetic acid

EP:

Elastin derived peptides

ERC:

Elastin receptor complex

GRKRK:

Gly-Arg-Lys-Arg-Lys

κE:

Kappa-elastin

MMP:

Matrix metalloproteinase

Neu-1:

Neuraminidase-1

NMR:

Nuclear magnetic resonance

PMSF:

Phenylmethylsulfonyl fluoride

PPCA:

Protective protein/cathepsin A

S-Gal:

Spliced galactosidase

uPA:

Urokinase plasminogen activator

VGVAPG:

Val-Gly-Val-Ala-Pro-Gly

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Acknowledgments

Simon Toupance is supported by a grant from the Ministry of Research. This work is supported by the Lions’s Clubs of Soissons, Villers-Cotterets and Crépy en Valois, by ACI Cancéropôle Grand Est 2007-2009 and by a grant from the CRP Santé of Luxembourg.

Conflict of interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. INSERM, UMRS 903, IFR53, Université de Reims Champagne-Ardenne, Reims, France

    Simon Toupance, Myriam Polette & Philippe Birembaut

  2. UMR CNRS 6237, IFR53, Université de Reims Champagne-Ardenne, Reims, France

    Simon Toupance, Bertrand Brassart, Fanja Rabenoelina & Laurent Debelle

  3. Microarray Center, CRP Santé, Luxembourg, Luxembourg

    Christelle Ghoneim & Laurent Vallar

  4. Laboratoire Pol Bouin, CHU Maison Blanche, 45 rue Cognacq-Jay, 51100, Reims, France

    Myriam Polette & Philippe Birembaut

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  1. Simon Toupance
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Correspondence to Philippe Birembaut.

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Philippe Birembaut and Laurent Debelle have contributed equally to this study.

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Toupance, S., Brassart, B., Rabenoelina, F. et al. Elastin-derived peptides increase invasive capacities of lung cancer cells by post-transcriptional regulation of MMP-2 and uPA. Clin Exp Metastasis 29, 511–522 (2012). https://doi.org/10.1007/s10585-012-9467-3

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  • DOI: https://doi.org/10.1007/s10585-012-9467-3

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