Itraconazole inhibits nuclear delivery of extracellular vesicle cargo by disrupting the entry of late endosomes into the nucleoplasmic reticulum
| Autor: | Stella Cascioferro, Kevin Huang, Simona Fontana, Riccardo Alessandro, Mark F. Santos, Goffredo Orazio Arena, Marta Moschetti, Gyunghwi Woo, Patrizia Diana, Denis Corbeil, Aurelio Lorico, Giulio Vistoli, Girolamo Cirrincione, Tony Huynh, Germana Rappa, Maria Antonietta Di Bella, Marshall R. Pope, Barbara Parrino, Jana Karbanová |
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| Přispěvatelé: | Santos, Mark F., Rappa, Germana, Karbanová, Jana, Fontana, Simona, Bella, Maria Antonietta Di, Pope, Marshall R., Parrino, Barbara, Cascioferro, Stella Maria, Vistoli, Giulio, Diana, Patrizia, Cirrincione, Girolamo, Arena, Goffredo O., Woo, Gyunghwi, Huang, Kevin, Huynh, Tony, Moschetti, Marta, Alessandro, Riccardo, Corbeil, Deni, Lorico, Aurelio |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular Histology Antifungal Agents Endosome Nuclear Envelope Nucleoplasmic reticulum Active Transport Cell Nucleus Vesicular Transport Proteins Host cell nucleoplasm Endosomes Endocytosis Fatty Acid-Binding Proteins Exosome Cell Line Extracellular Vesicles Cell Movement Settore BIO/13 - Biologia Applicata Humans cancer exosome metastasis endosome Research Articles Cholestenones micro‐vesicle QH573-671 Chemistry rab7 GTP-Binding Proteins Cell Biology Extracellular vesicle Saponins Cell biology Ketoconazole Cancer cell intercellular communication nucleoplasmic reticulum cancer endosome exosome intercellular communication metastasis micro-vesicle nucleoplasmicreticulum Itraconazole Cytology Intracellular Research Article |
| Zdroj: | Journal of Extracellular Vesicles, Vol 10, Iss 10, Pp n/a-n/a (2021) Journal of Extracellular Vesicles |
| ISSN: | 2001-3078 |
| Popis: | Extracellular vesicles (EVs) are mediators of intercellular communication under both healthy and pathological conditions, including the induction of pro‐metastatic traits, but it is not yet known how and where functional cargoes of EVs are delivered to their targets in host cell compartments. We have described that after endocytosis, EVs reach Rab7+ late endosomes and a fraction of these enter the nucleoplasmic reticulum and transport EV biomaterials to the host cell nucleoplasm. Their entry therein and docking to outer nuclear membrane occur through a tripartite complex formed by the proteins VAP‐A, ORP3 and Rab7 (VOR complex). Here, we report that the antifungal compound itraconazole (ICZ), but not its main metabolite hydroxy‐ICZ or ketoconazole, disrupts the binding of Rab7 to ORP3–VAP‐A complexes, leading to inhibition of EV‐mediated pro‐metastatic morphological changes including cell migration behaviour of colon cancer cells. With novel, smaller chemical drugs, inhibition of the VOR complex was maintained, although the ICZ moieties responsible for antifungal activity and interference with intracellular cholesterol distribution were removed. Knowing that cancer cells hijack their microenvironment and that EVs derived from them determine the pre‐metastatic niche, small‐sized inhibitors of nuclear transfer of EV cargo into host cells could find cancer therapeutic applications, particularly in combination with direct targeting of cancer cells. |
| Databáze: | OpenAIRE |
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