MCM2-7 complex is a novel druggable target for neuroendocrine prostate cancer.
Animals
Carcinoma, Neuroendocrine
/ metabolism
Cell Line, Tumor
Gene Expression Regulation, Neoplastic
/ physiology
Humans
Male
Mice
Mice, Inbred NOD
Mice, SCID
Minichromosome Maintenance Complex Component 2
/ metabolism
Minichromosome Maintenance Complex Component 7
/ metabolism
Minichromosome Maintenance Proteins
/ metabolism
Neuroendocrine Tumors
/ metabolism
PC-3 Cells
Prostate
/ metabolism
Prostatic Neoplasms
/ metabolism
Receptors, Androgen
/ metabolism
Signal Transduction
/ physiology
Up-Regulation
/ physiology
Xenograft Model Antitumor Assays
/ methods
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
25 06 2021
25 06 2021
Historique:
received:
14
03
2021
accepted:
09
06
2021
entrez:
26
6
2021
pubmed:
27
6
2021
medline:
6
11
2021
Statut:
epublish
Résumé
Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer that rarely develops de novo in primary tumors and is commonly acquired during the development of treatment resistance. NEPC is characterized by gain of neuroendocrine markers and loss of androgen receptor (AR), making it resistant to current therapeutic strategies targeting the AR signaling axis. Here, we report that MCM2, MCM3, MCM4, and MCM6 (MCM2/3/4/6) are elevated in human NEPC and high levels of MCM2/3/4/6 are associated with liver metastasis and poor survival in prostate cancer patients. MCM2/3/4/6 are four out of six proteins that form a core DNA helicase (MCM2-7) responsible for unwinding DNA forks during DNA replication. Inhibition of MCM2-7 by treatment with ciprofloxacin inhibits NEPC cell proliferation and migration in vitro, significantly delays NEPC tumor xenograft growth, and partially reverses the neuroendocrine phenotype in vivo. Our study reveals the clinical relevance of MCM2/3/4/6 proteins in NEPC and suggests that inhibition of MCM2-7 may represent a new therapeutic strategy for NEPC.
Identifiants
pubmed: 34172788
doi: 10.1038/s41598-021-92552-x
pii: 10.1038/s41598-021-92552-x
pmc: PMC8233352
doi:
Substances chimiques
Receptors, Androgen
0
MCM2 protein, human
EC 3.6.4.12
MCM7 protein, human
EC 3.6.4.12
Minichromosome Maintenance Complex Component 2
EC 3.6.4.12
Minichromosome Maintenance Complex Component 7
EC 3.6.4.12
Minichromosome Maintenance Proteins
EC 3.6.4.12
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
13305Subventions
Organisme : NCI NIH HHS
ID : P50 CA097186
Pays : United States
Organisme : NCI NIH HHS
ID : R37 CA240822
Pays : United States
Organisme : NIH HHS
ID : S10 OD023518
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA196387
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA244281
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA163227
Pays : United States
Organisme : NCI NIH HHS
ID : R03 CA230819
Pays : United States
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