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Prostate cancer-derived exosomes promote osteoblast differentiation and activity through phospholipase D2.

Authors
  • Borel, Mathieu1
  • Lollo, Giovanna2
  • Magne, David1
  • Buchet, René1
  • Brizuela, Leyre1
  • Mebarek, Saida3
  • 1 Univ Lyon, Univ Claude Bernard Lyon 1, CNRS, UMR 5246, ICBMS, F-69622 Lyon, France. , (France)
  • 2 Univ Lyon, Univ Claude Bernard Lyon 1, CNRS, UMR 5007, LAGEPP, F-69622 Lyon, France. , (France)
  • 3 Univ Lyon, Univ Claude Bernard Lyon 1, CNRS, UMR 5246, ICBMS, F-69622 Lyon, France. Electronic address: [email protected] , (France)
Type
Published Article
Journal
Biochimica et biophysica acta. Molecular basis of disease
Publication Date
Dec 01, 2020
Volume
1866
Issue
12
Pages
165919–165919
Identifiers
DOI: 10.1016/j.bbadis.2020.165919
PMID: 32800947
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Prostate cancer (PCa) is the most frequent cancer in men aged 65 and over. PCa mainly metastasizes in the bone, forming osteosclerotic lesions, inducing pain, fractures, and nerve compression. Cancer cell-derived exosomes participate in the metastatic spread, ranging from oncogenic reprogramming to the formation of pre-metastatic niches. Moreover, exosomes were recently involved in the dialog between PCa cells and the bone metastasis microenvironment. Phospholipase D (PLD) isoforms PLD1/2 catalyze the hydrolysis of phosphatidylcholine to yield phosphatidic acid (PA), regulating tumor progression and metastasis. PLD is suspected to play a role in exosomes biogenesis. We aimed to determine whether PCa-derived exosomes, through PLD, interact with the bone microenvironment, especially osteoblasts, during the metastatic process. Here we demonstrate for the first time that PLD2 is present in exosomes of C4-2B and PC-3 cells. C4-2B-derived exosomes activate proliferation and differentiation of osteoblasts models, by stimulating ERK 1/2 phosphorylation, by increasing the tissue-nonspecific alkaline phosphatase activity and the expression of osteogenic differentiation markers. Contrariwise, when C4-2B exosomes are generated in the presence of halopemide, a PLD pan-inhibitor, they lose their ability to stimulate osteoblasts. Furthermore, the number of released exosomes diminishes significantly (-40%). When the PLD product PA is combined with halopemide, exosome secretion is fully restored. Taken together, our results indicate that PLD2 stimulates exosome secretion in PCa cell models as well as their ability to increase osteoblast activity. Thus, PLD2 could be considered as a potent player in the establishment of PCa bone metastasis acting through tumor cell derived-exosomes. Copyright © 2020 Elsevier B.V. All rights reserved.

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