Journal article
Itraconazole inhibits nuclear delivery of extracellular vesicle cargo by disrupting the entry of late endosomes into the nucleoplasmic reticulum
Journal of extracellular vesicles, Vol.10(10), e12132
08/2021
DOI: 10.1002/jev2.12132
PMCID: PMC8363911
PMID: 34429859
Abstract
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.
Details
- Title: Subtitle
- Itraconazole inhibits nuclear delivery of extracellular vesicle cargo by disrupting the entry of late endosomes into the nucleoplasmic reticulum
- Creators
- Mark F Santos - Touro University NevadaGermana Rappa - Touro University NevadaJana Karbanová - TU DresdenSimona Fontana - University of PalermoMaria Antonietta Di Bella - Department of Biomedicine, Neurosciences and Advanced Diagnostics University of Palermo Palermo ItalyMarshall R Pope - University of IowaBarbara Parrino - University of PalermoStella Maria Cascioferro - University of PalermoGiulio Vistoli - University of MilanPatrizia Diana - University of PalermoGirolamo Cirrincione - University of PalermoGoffredo O Arena - McGill UniversityGyunghwi Woo - Touro University NevadaKevin Huang - Touro University NevadaTony Huynh - Touro University NevadaMarta Moschetti - University of PalermoRiccardo Alessandro - University of PalermoDenis Corbeil - TU DresdenAurelio Lorico - Touro University Nevada
- Resource Type
- Journal article
- Publication Details
- Journal of extracellular vesicles, Vol.10(10), e12132
- DOI
- 10.1002/jev2.12132
- PMID
- 34429859
- PMCID
- PMC8363911
- ISSN
- 2001-3078
- eISSN
- 2001-3078
- Language
- English
- Date published
- 08/2021
- Academic Unit
- Medicine Administration
- Record Identifier
- 9984627190802771
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