Cytoplasmic Localization of Prostate-Specific Membrane Antigen Inhibitors May Confer Advantages for Targeted Cancer Therapies.
Animals
Antigens, Surface
/ metabolism
Cell Membrane
/ metabolism
Clathrin
/ metabolism
Cytoplasm
/ metabolism
Endocytosis
Endosomes
/ metabolism
Glutamate Carboxypeptidase II
/ antagonists & inhibitors
Heterografts
Humans
Male
Mice
Microscopy, Fluorescence
/ methods
Molecular Targeted Therapy
/ methods
Nanotechnology
/ methods
Peptidomimetics
/ pharmacokinetics
Prostatic Neoplasms
/ drug therapy
Staining and Labeling
Journal
Cancer research
ISSN: 1538-7445
Titre abrégé: Cancer Res
Pays: United States
ID NLM: 2984705R
Informations de publication
Date de publication:
15 04 2021
15 04 2021
Historique:
received:
28
05
2020
revised:
29
12
2020
accepted:
04
02
2021
pubmed:
25
2
2021
medline:
14
9
2021
entrez:
24
2
2021
Statut:
ppublish
Résumé
Targeted imaging and therapy approaches based on novel prostate-specific membrane antigen (PSMA) inhibitors have fundamentally changed the treatment regimen of prostate cancer. However, the exact mechanism of PSMA inhibitor internalization has not yet been studied, and the inhibitors' subcellular fate remains elusive. Here, we investigated the intracellular distribution of peptidomimetic PSMA inhibitors and of PSMA itself by stimulated emission depletion (STED) nanoscopy, applying a novel nonstandard live cell staining protocol. Imaging analysis confirmed PSMA cluster formation at the cell surface of prostate cancer cells and clathrin-dependent endocytosis of PSMA inhibitors. Following the endosomal pathway, PSMA inhibitors accumulated in prostate cancer cells at clinically relevant time points. In contrast with PSMA itself, PSMA inhibitors were found to eventually distribute homogeneously in the cytoplasm, a molecular condition that promises benefits for treatment as cytoplasmic and in particular perinuclear enrichment of the radionuclide carriers may better facilitate the radiation-mediated damage of cancerous cells. This study is the first to reveal the subcellular fate of PSMA/PSMA inhibitor complexes at the nanoscale and aims to inspire the development of new approaches in the field of prostate cancer research, diagnostics, and therapeutics. SIGNIFICANCE: This study uses STED fluorescence microscopy to reveal the subcellular fate of PSMA/PSMA inhibitor complexes near the molecular level, providing insights of great clinical interest and suggestive of advantageous targeted therapies. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/8/2234/F1.large.jpg.
Identifiants
pubmed: 33622696
pii: 0008-5472.CAN-20-1624
doi: 10.1158/0008-5472.CAN-20-1624
doi:
Substances chimiques
Antigens, Surface
0
Clathrin
0
Peptidomimetics
0
FOLH1 protein, human
EC 3.4.17.21
Glutamate Carboxypeptidase II
EC 3.4.17.21
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2234-2245Informations de copyright
©2021 American Association for Cancer Research.
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