EDIL3 promotes epithelial–mesenchymal transition and paclitaxel resistance through its interaction with integrin αVβ3 in cancer cells

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.

Pathogenesis of Enamel-Renal Syndrome Associated Gingival Fibromatosis: A Proteomic Approach

“…EDIL3 is an ECM protein that acts as a pro-angiogenic and antiinflammatory factor. EDIL3 was shown to activate TGFb signaling (68) and its capacity to bind calcium ions and extracellular vesicles (69) suggests a role in calcification.…”

Molecular mechanisms of chemo‐ and radiotherapy resistance and the potential implications for cancer treatment

“…Moreover, EDIL3 may be involved in EMT and Taxol resistance in cancer cells through autocrine or paracrine signaling. Cilengitide blocks the EDIL3‐integrin αVβ3 interaction to restore sensitivity to Taxol and mitigates EMT in Taxol‐resistant cancer cells 218 . Exploring the genetic basis of Taxol resistance in cancer cells is expected to provide theoretical evidence for a better understanding of the drug response in esophageal cancer.…”

“…Comparison of the differential gene expression patterns between Taxol‐resistant and Taxol‐sensitive breast cancer cells revealed upregulation of EGF‐like repetition and disoidini‐like domain protein 3 (EDIL3), 218 which encodes an extracellular matrix protein and has been identified as a new regulator of EMT. Knockout of the EDIL3 gene inhibits EMT and sensitizes cells to Taxol; by contrast, overexpression of EDIL3 was reported to induce EMT and Taxol resistance through its interaction with integrin αVβ3.…”

Serine and one-carbon metabolisms bring new therapeutic venues in prostate cancer

“…In the pathogenesis of prostate cancer, the initial pathogenetic event might be considered the dependency from the androgen stimulation [46][47][48][49][50], but many more molecular alterations have been found associated to its progression [51][52][53][54][55] as well as to the development of specific clinical features of the disease such as bone metastasis [56] or studied as potential therapeutic targets [57]. The microbiome has also been shown to impact on the pathogenesis of this kind of cancer [58][59][60][61][62], also due to development of algorithms allowing to interpret its role in the context of a disease [63][64][65][66][67].…”