Membrane metalloendopeptidase suppresses prostate carcinogenesis by attenuating effects of gastrin-releasing peptide on stem/progenitor cells.
Journal
Oncogenesis
ISSN: 2157-9024
Titre abrégé: Oncogenesis
Pays: United States
ID NLM: 101580004
Informations de publication
Date de publication:
23 Mar 2020
23 Mar 2020
Historique:
received:
29
01
2020
accepted:
05
03
2020
revised:
02
03
2020
entrez:
25
3
2020
pubmed:
25
3
2020
medline:
25
3
2020
Statut:
epublish
Résumé
Aberrant neuroendocrine signaling is frequent yet poorly understood feature of prostate cancers. Membrane metalloendopeptidase (MME) is responsible for the catalytic inactivation of neuropeptide substrates, and is downregulated in nearly 50% of prostate cancers. However its role in prostate carcinogenesis, including formation of castration-resistant prostate carcinomas, remains uncertain. Here we report that MME cooperates with PTEN in suppression of carcinogenesis by controlling activities of prostate stem/progenitor cells. Lack of MME and PTEN results in development of adenocarcinomas characterized by propensity for vascular invasion and formation of proliferative neuroendocrine clusters after castration. Effects of MME on prostate stem/progenitor cells depend on its catalytic activity and can be recapitulated by addition of the MME substrate, gastrin-releasing peptide (GRP). Knockdown or inhibition of GRP receptor (GRPR) abrogate effects of MME deficiency and delay growth of human prostate cancer xenografts by reducing the number of cancer-propagating cells. In sum, our study provides a definitive proof of tumor-suppressive role of MME, links GRP/GRPR signaling to the control of prostate stem/progenitor cells, and shows how dysregulation of such signaling may promote formation of castration-resistant prostate carcinomas. It also identifies GRPR as a valuable target for therapies aimed at eradication of cancer-propagating cells in prostate cancers with MME downregulation.
Identifiants
pubmed: 32205838
doi: 10.1038/s41389-020-0222-3
pii: 10.1038/s41389-020-0222-3
pmc: PMC7090072
doi:
Types de publication
Journal Article
Langues
eng
Pagination
38Subventions
Organisme : U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
ID : CA197160
Organisme : New York State Stem Cell Science (NYSTEM)
ID : C028125
Organisme : NCI NIH HHS
ID : R01 CA197160
Pays : United States
Organisme : New York State Stem Cell Science (NYSTEM)
ID : C023050
Organisme : U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
ID : CA72717
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