Structural characterization and<i>in vivo</i>pro-tumor properties of a highly conserved matrikine

silva, Jordan Da; Lameiras, Pédro; Beljebbar, A.; Berquand, Alexandre; Villemin, Matthieu; Ramont, Laurent; Dukic, Sylvain; Nuzillard, Jean‐Marc; Molinari, Michaël; Gautier, Mathieu; Brassart‐Pasco, Sylvie; Brassart, Bertrand

doi:10.18632/oncotarget.24894

Cited by 22 publications

(31 citation statements)

References 53 publications

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“…Matrikines like EDPs were shown to promote tumour cell invasion. 4,5,7 The present study provides evidence that EDP treatment of tumour cells induces a switch from a mesenchymal cell phenotype to an amoeboid-like phenotype characterised by a highly dynamic membrane blebbing and by extracellular vesicle shedding. These findings may explain why EDPs favour tumour cell invasion and metastasis.…”

Section: Discussionmentioning

confidence: 53%

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Tumour cell blebbing and extracellular vesicle shedding: key role of matrikines and ribosomal protein SA

Brassart

silva

et al. 2019

Br J Cancer

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BACKGROUND: Carcinogenesis occurs in elastin-rich tissues and leads to local inflammation and elastolytic proteinase release. This contributes to bioactive matrix fragment (Matrikine) accumulation like elastin degradation products (EDP) stimulating tumour cell invasive and metastatic properties. We previously demonstrate that EDPs exert protumoural activities through Hsp90 secretion to stabilised extracellular proteinases. METHODS: EDP influence on cancer cell blebbing and extracellular vesicle shedding were examined with a videomicroscope coupled with confocal Yokogawa spinning disk, by transmission electron microscopy, scanning electron microscopy and confocal microscopy. The ribosomal protein SA (RPSA) elastin receptor was identified after affinity chromatography by western blotting and cell immunolocalisation. mRNA expression was studied using real-time PCR. SiRNA were used to confirm the essential role of RPSA. RESULTS: We demonstrate that extracellular matrix degradation products like EDPs induce tumour amoeboid phenotype with cell membrane blebbing and shedding of extracellular vesicle containing Hsp90 and proteinases in the extracellular space. EDPs influence intracellular calcium influx and cytoskeleton reorganisation. Among matrikines, VGVAPG and AGVPGLGVG peptides reproduced EDP effects through RPSA binding. CONCLUSIONS: Our data suggests that matrikines induce cancer cell blebbing and extracellular vesicle release through RPSA binding, favouring dissemination, cell-to-cell communication and growth of cancer cells in metastatic sites.

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Section: Discussionmentioning

confidence: 53%

“…Among EDPs, VGVAPG and AGVPGLGVG peptides were reported to stimulate cell invasion. [4][5][6][7] They increase MMP-2, MT1-MMP, uPA and Hsp90 secretion by cancer cells. Hsp90 was shown to interact with many extracellular proteins involved in cancer progression and metastasis and to be of critical importance.…”

Section: Introductionmentioning

confidence: 99%

Tumour cell blebbing and extracellular vesicle shedding: key role of matrikines and ribosomal protein SA

Brassart

silva

et al. 2019

Br J Cancer

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“…AGVPGLGVG) plays a key role in tumor progression by promoting tumor cell blebbing and extracellular vesicle shedding following its interaction with the ribosomal protein SA (17). The structure of hN5 has been analyzed previously by CD, FT-IR and NMR spectroscopies (16). This report concluded that the structure of the peptide was a mixture of random coils and b-turns.…”

Section: Discussionmentioning

confidence: 95%

“…However, AGVPGLGVG induces angiogenesis, tumor progression, secretion of proteases higher than other EDPs in carcinomas. Moreover, in vitro, it behaves like amyloid-like peptides harboring the XGGXG motif by forming cross b-sheets at the supramolecular level (16). Very recently, Brassart and colleagues have shown that the receptor mediating AGVPGLGVG biological effects, and identified as lactose-insensitive, is the Ribosomal Protein SA (17).…”

Section: Introductionmentioning

confidence: 99%

Structural analysis of nonapeptides derived from elastin

Hernández¹,

Crowet²,

Thiery³

et al. 2019

Preprint

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AbstractElastin-derived peptides are released from the extracellular matrix remodeling by numerous proteases and seem to regulate many biological processes, notably cancer progression. The canonical elastin peptide is VGVAPG which harbors the XGXXPG consensus pattern allowing interaction with the elastin receptor complex located at the surface of cells. Besides these elastokines, another class of peptides has been identified. This group of bioactive elastin peptides presents the XGXPGXGXG consensus sequence but the reason for their bioactivity remains unexplained. In order to better understand their nature and structure-function relationships, herein we searched the current databases for this nonapeptide motif and observed that the XGXPGXGXG elastin peptides define a specific group of tandemly repeated patterns. Further, we focused on four tandemly repeated human elastin nonapeptides, i.e. AGIPGLGVG, VGVPGLGVG, AGVPGLGVG and AGVPGFGAG. These peptides were analysed by means of optical spectroscopies and molecular dynamics. UV-circular dichroism and Raman spectra are consistent with a conformational equilibrium between β-turn, β-strand and random chain secondary elements in aqueous media. This equilibrium was found to be concentration-independent. Quantitative analysis of their conformations suggested that turns corresponded to half of the total population of structural elements while the remaining half was equally distributed between β-strand and unordered chains. These distributions were confirmed by molecular dynamics simulations. Altogether, our data suggest that these peptides harbor a type II β-turn located in their central part. We hypothesize that this structural element could explain their specific bioactivity.Statement of SignificanceElastin fragmentation products, the so-called elastin peptides, may exhibit a bioactivity towards normal and tumor cells. This phenomenon depends on the sequence motif they harbor. While XGXXPG sequences bioactivity is explained by the presence of a type VIII β-turn allowing interaction with the elastin receptor complex, the structural reasons for XGXPGXGXG specific activity remain unexplained. Using data mining, we show that elastin nonapeptides define a specific class of tandemly repeated features. Further, spectroscopic and numerical simulations methods suggest the presence of a type II β-turn in their conformation. This structural element could explain their bioactivity.

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“…In recent years, the basement membrane (BM), a specialized extracellular matrix (ECM), has been recognized as a key regulator of cell behavior, and not only as an architectural support. BM is an important structural and functional component of blood vessels (Silva et al, 2018). Several BM components were reported to largely participate in the regulation of tumor angiogenesis (Kalluri, 2003).…”

Section: Introductionmentioning

confidence: 99%

Angiogenesis Inhibition by a Short 13 Amino Acid Peptide Sequence of Tetrastatin, the α4(IV) NC1 Domain of Collagen IV

Vautrin-Glabik

Devy

Bour

et al. 2020

Front. Cell Dev. Biol.

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Angiogenesis is defined as the formation of new capillaries by sprouting from the pre-existing microvasculature. It occurs in physiological and pathological processes particularly in tumor growth and metastasis. α1, α2, α3, and α6 NC1 domains from type IV collagen were reported to inhibit tumor angiogenesis. We previously demonstrated that the α4 NC1 domain from type IV collagen, named Tetrastatin, inhibited tumor growth in a mouse melanoma model. The inhibitory activity was located in a 13 amino acid sequence named QS-13. In the present paper, we demonstrate that QS-13 decreases VEGF-induced-angiogenesis in vivo using the Matrigel plug model. Fluorescence molecular tomography allows the measurement of a 65% decrease in Matrigel plug angiogenesis following QS-13 administration. The results are confirmed by CD31 microvessel density analysis on Matrigel plug slices. QS-13 peptide decreases Human Umbilical Vein Endothelial Cells (HUVEC) migration and pseudotube formation in vitro. Relevant QS-13 conformations were obtained from molecular dynamics simulations and docking. A putative interaction of QS-13 with α 5 β 1 integrin was investigated. The interaction was confirmed by affinity chromatography, solid phase assay, and surface plasmon resonance. QS-13 binding site on α 5 β 1 integrin is located in close vicinity to the RGD binding site, as demonstrated by competition assays. Collectively, our results suggest that QS-13 exhibits a mighty anti-angiogenic activity that could be used in cancer treatment and other pathologies with excessive angiogenesis such as hemangioma, psoriasis or diabetes.

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Structural characterization andin vivopro-tumor properties of a highly conserved matrikine

Cited by 22 publications

References 53 publications

Tumour cell blebbing and extracellular vesicle shedding: key role of matrikines and ribosomal protein SA

Tumour cell blebbing and extracellular vesicle shedding: key role of matrikines and ribosomal protein SA

Structural analysis of nonapeptides derived from elastin

Angiogenesis Inhibition by a Short 13 Amino Acid Peptide Sequence of Tetrastatin, the α4(IV) NC1 Domain of Collagen IV

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