Itraconazole inhibits nuclear delivery of extracellular vesicle cargo by disrupting the entry of late endosomes into the nucleoplasmic reticulum

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Mark F Santos - , Touro University - Nevada (Author)
  • Germana Rappa - , Touro University - Nevada (Author)
  • Jana Karbanová - , Research Group Tissue Engineering, Tissue Engineering (Research Group), Biotechnology Center (Author)
  • Simona Fontana - , University of Palermo (Author)
  • Maria Antonietta Di Bella - , University of Palermo (Author)
  • Marshall R Pope - , University of Iowa (Author)
  • Barbara Parrino - , University of Palermo (Author)
  • Stella Maria Cascioferro - , University of Palermo (Author)
  • Giulio Vistoli - , University of Milan - Bicocca (Author)
  • Patrizia Diana - , University of Palermo (Author)
  • Girolamo Cirrincione - , University of Palermo (Author)
  • Goffredo O Arena - , McGill University Health Centre (Author)
  • Gyunghwi Woo - , Touro University - Nevada (Author)
  • Kevin Huang - , Touro University - Nevada (Author)
  • Tony Huynh - , Touro University - Nevada (Author)
  • Marta Moschetti - , University of Palermo (Author)
  • Riccardo Alessandro - , University of Palermo (Author)
  • Denis Corbeil - , Research Group Tissue Engineering, Tissue Engineering (Research Group), Biotechnology Center (Author)
  • Aurelio Lorico - , Touro University - Nevada (Author)

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 languageEnglish
Article numbere12132
JournalJournal of extracellular vesicles
Volume10
Issue number10
Publication statusPublished - Aug 2021
Peer-reviewedYes

External IDs

PubMedCentral PMC8363911
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