Hyperactive mTOR induces neuroendocrine differentiation in prostate cancer cell with concurrent up-regulation of IRF1.
Prostate
; 77(15): 1489-1498, 2017 Nov.
Article
em En
| MEDLINE
| ID: mdl-28905415
ABSTRACT
BACKGROUND:
Neuroendocrine-differentiated prostate cancer (NEPCa) is refractory to androgen deprivation therapy and shows a poor prognosis. The underlying mechanisms responsible for neuroendocrine differentiation (NED) are yet to be clarified. In this study, we investigated the role of mammalian target of rapamycin (mTOR) in NEPCa.METHODS:
We utilized a gain-of-function analysis by establishing a human PCa LNCaP stable line that expresses hyperactive mTOR (LNCaP-mTOR). Then, we employed a comprehensive mass spectrometric analysis to identify a key transcription factor in LNCaP-mTOR, followed by a loss-of-function analysis using CRISPR/Cas system.RESULTS:
The activation of mTOR induced NED. We observed significant cell growth arrest in NED of LNCaP-mTOR, which accompanied increased expression of p21WAF1/CIP1 . A comprehensive mass spectrometric analysis identified interferon regulatory factor 1 (IRF1) as a key transcription factor in growth arrest of LNCaP-mTOR. The disruption of IRF1 gene in LNCaP-mTOR reversed cell growth arrest along with the suppression of its target p21WAF1/CIP1 . These results indicate that the growth arrest in NED is at least in part dependent on IRF1 through the induction of p21WAF1/CIP1 .CONCLUSIONS:
We identified active mTOR as a novel inducer of NED, and elucidated a mechanism underlying the malignant transformation of NEPCa by recapitulating NED in vitro.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Próstata
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Tumores Neuroendócrinos
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Fator Regulador 1 de Interferon
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Serina-Treonina Quinases TOR
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Prostate
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Japão