EDIL3 promotes epithelial\u2013mesenchymal transition and paclitaxel resistance through its interaction with integrin \u03b1V\u03b23 in cancer cells

J Gasca,F Romero,M L Flores,C Sáez,M A Japón,M E Sáez,I Barragán,M Ruíz-Borrego,R Jiménez-Guerrero,M Tortolero

doi:10.1038/s41420-020-00322-x

Abstract

Epithelial–mesenchymal transition (EMT) has recently been associated with tumor progression, metastasis, and chemotherapy resistance in several tumor types. We performed a differential gene expression analysis comparing paclitaxel-resistant vs. paclitaxel-sensitive breast cancer cells that showed the upregulation of EDIL3 (EGF Like Repeats and Discoidin I Like Domains Protein 3). This gene codifies an extracellular matrix protein that has been identified as a novel regulator of EMT, so we studied its role in tumor progression and paclitaxel response. Our results demonstrated that EDIL3 expression levels were increased in paclitaxel-resistant breast and prostate cancer cells, and in subsets of high-grade breast and prostate tumors. Moreover, we observed that EDIL3 modulated the expression of EMT markers and this was impaired by cilengitide, which blocks the EDIL3–integrin αVβ3 interaction. EDIL3 knockdown reverted EMT and sensitized cells to paclitaxel. In contrast, EDIL3 overexpression or the culture of cells in the presence of EDIL3-enriched medium induced EMT and paclitaxel resistance. Adding cilengitide resensitized these cells to paclitaxel treatment. In summary, EDIL3 may contribute to EMT and paclitaxel resistance through autocrine or paracrine signaling in cancer cells. Blockade of EDIL3–integrin αVβ3 interaction by cilengitide restores sensitivity to paclitaxel and reverts EMT in paclitaxel-resistant cancer cells. Combinations of cilengitide and taxanes could be beneficial in the treatment of subsets of breast and prostate cancers.

Highlights

Epithelial–mesenchymal transition (EMT) is the process by which epithelial cells loose the adherent and tight junctions that keep them in contact with their neighbor cells to gain a mesenchymal phenotype
Since EDIL3 interacts with integrin αVβ3 and other ligands of this integrin are secreted to the extracellular matrix (ECM) and present an autocrine regulation mechanism, we investigated whether EDIL3 was secreted to the medium by breast cancer cells expressing different levels of EDIL3
We examined the effect of cilengitide, a cyclic pentapeptide whose chemical structure is based on the RGD sequence, which blocks the interaction of EDIL3 with integrin αVβ3 (29), on the secretion of EDIL3 and the expression of EMT markers

Summary

Introduction

Epithelial–mesenchymal transition (EMT) is the process by which epithelial cells loose the adherent and tight junctions that keep them in contact with their neighbor cells to gain a mesenchymal phenotype. This transition favors an increased mobility, migration, or invasion. EMT is a complex process involving several transcription factors, cell-surface and cytoskeletal proteins, components of the extracellular matrix (ECM), and numerous signaling cadherin expression that provides the physical structure for both cell–cell junctions and for the recruitment of signaling complexes in epithelial cells[2,3].

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Conclusion