DDX5 mRNA-targeting antisense oligonucleotide as a new promising therapeutic in combating castration-resistant prostate cancer.
DDX5
DNA damage response (DDR)
Hsp27
antisense oligonucleotides (ASOs)
castration-resistant prostate cancer (CRPC)
protein interactions
therapeutic ressistance
Journal
Molecular therapy : the journal of the American Society of Gene Therapy
ISSN: 1525-0024
Titre abrégé: Mol Ther
Pays: United States
ID NLM: 100890581
Informations de publication
Date de publication:
01 02 2023
01 02 2023
Historique:
received:
03
12
2021
revised:
26
06
2022
accepted:
09
08
2022
pmc-release:
01
02
2024
pubmed:
16
8
2022
medline:
7
2
2023
entrez:
15
8
2022
Statut:
ppublish
Résumé
The heat shock protein 27 (Hsp27) has emerged as a principal factor of the castration-resistant prostate cancer (CRPC) progression. Also, an antisense oligonucleotide (ASO) against Hsp27 (OGX-427 or apatorsen) has been assessed in different clinical trials. Here, we illustrate that Hsp27 highly regulates the expression of the human DEAD-box protein 5 (DDX5), and we define DDX5 as a novel therapeutic target for CRPC treatment. DDX5 overexpression is strongly correlated with aggressive tumor features, notably with CRPC. DDX5 downregulation using a specific ASO-based inhibitor that acts on DDX5 mRNAs inhibits cell proliferation in preclinical models, and it particularly restores the treatment sensitivity of CRPC. Interestingly, through the identification and analysis of DDX5 protein interaction networks, we have identified some specific functions of DDX5 in CRPC that could contribute actively to tumor progression and therapeutic resistance. We first present the interactions of DDX5 and the Ku70/80 heterodimer and the transcription factor IIH, thereby uncovering DDX5 roles in different DNA repair pathways. Collectively, our study highlights critical functions of DDX5 contributing to CRPC progression and provides preclinical proof of concept that a combination of ASO-directed DDX5 inhibition with a DNA damage-inducing therapy can serve as a highly potential novel strategy to treat CRPC.
Identifiants
pubmed: 35965411
pii: S1525-0016(22)00493-2
doi: 10.1016/j.ymthe.2022.08.005
pmc: PMC9931527
pii:
doi:
Substances chimiques
Oligonucleotides, Antisense
0
RNA, Messenger
0
HSP27 Heat-Shock Proteins
0
Ddx5 protein, human
EC 3.6.1.-
DEAD-box RNA Helicases
EC 3.6.4.13
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
471-486Informations de copyright
Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare to have no financial, personal, or professional competing interest and no conflict of interest.
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