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 - , College of Medicine Touro University Nevada Henderson Nevada USA. (Author)
  • Germana Rappa - , College of Medicine Touro University Nevada Henderson Nevada USA. (Author)
  • Jana Karbanová - , Research Group Tissue Engineering, Tissue Engineering (Research Group) (Author)
  • Simona Fontana - , Neurosciences and Advanced Diagnostics University of Palermo Palermo Italy (Author)
  • Maria Antonietta Di Bella - , Neurosciences and Advanced Diagnostics University of Palermo Palermo Italy (Author)
  • Marshall R Pope - , Proteomics Facility University of Iowa Iowa City Iowa USA. (Author)
  • Barbara Parrino - , Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche Università degli Studi di Palermo Palermo Italy (Author)
  • Stella Maria Cascioferro - , Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche Università degli Studi di Palermo Palermo Italy (Author)
  • Giulio Vistoli - , University of Milan - Bicocca (Author)
  • Patrizia Diana - , Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche Università degli Studi di Palermo Palermo Italy (Author)
  • Girolamo Cirrincione - , Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche Università degli Studi di Palermo Palermo Italy (Author)
  • Goffredo O Arena - , McGill University Health Centre (MUHC) (Author)
  • Gyunghwi Woo - , College of Medicine Touro University Nevada Henderson Nevada USA. (Author)
  • Kevin Huang - , College of Medicine Touro University Nevada Henderson Nevada USA. (Author)
  • Tony Huynh - , College of Medicine Touro University Nevada Henderson Nevada USA. (Author)
  • Marta Moschetti - , Neurosciences and Advanced Diagnostics University of Palermo Palermo Italy (Author)
  • Riccardo Alessandro - , Neurosciences and Advanced Diagnostics University of Palermo Palermo Italy (Author)
  • Denis Corbeil - , Research Group Tissue Engineering, Tissue Engineering (Research Group) (Author)
  • Aurelio Lorico - , College of Medicine Touro University Nevada Henderson Nevada USA. (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

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