Itraconazole inhibits nuclear delivery of extracellular vesicle cargo by disrupting the entry of late endosomes into the nucleoplasmic reticulum
Research output: Contribution to journal › Research article › Contributed › peer-review
Contributors
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
Original language | English |
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Article number | e12132 |
Journal | Journal of extracellular vesicles |
Volume | 10 |
Issue number | 10 |
Publication status | Published - Aug 2021 |
Peer-reviewed | Yes |
External IDs
PubMedCentral | PMC8363911 |
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Scopus | 85112853594 |
ORCID | /0000-0003-1181-3659/work/142252255 |
ORCID | /0000-0001-7687-0983/work/142253732 |
Keywords
Sustainable Development Goals
Keywords
- Active Transport, Cell Nucleus, Antifungal Agents/pharmacology, Cell Line, Cell Movement/drug effects, Cholestenones/pharmacology, Endocytosis, Endosomes/metabolism, Extracellular Vesicles/drug effects, Fatty Acid-Binding Proteins/chemistry, Humans, Itraconazole/pharmacology, Ketoconazole/pharmacology, Models, Molecular, Nuclear Envelope/metabolism, Saponins/pharmacology, Vesicular Transport Proteins/chemistry, rab7 GTP-Binding Proteins/chemistry