Effective targeting of RNA polymerase I in treatment-resistant prostate cancer.
Prostate
; 79(16): 1837-1851, 2019 12.
Article
em En
| MEDLINE
| ID: mdl-31524299
ABSTRACT
BACKGROUND:
Advanced prostate cancers depend on protein synthesis for continued survival and accelerated rates of metabolism for growth. RNA polymerase I (Pol I) is the enzyme responsible for ribosomal RNA (rRNA) transcription and a rate-limiting step for ribosome biogenesis. We have shown using a specific and sensitive RNA probe for the 45S rRNA precursor that rRNA synthesis is increased in prostate adenocarcinoma compared to nonmalignant epithelium. We have introduced a first-in-class Pol I inhibitor, BMH-21, that targets cancer cells of multiple origins, and holds potential for clinical translation.METHODS:
The effect of BMH-21 was tested in prostate cancer cell lines and in prostate cancer xenograft and mouse genetic models.RESULTS:
We show that BMH-21 inhibits Pol I transcription in metastatic, castration-resistant, and enzalutamide treatment-resistant prostate cancer cell lines. The genetic abrogation of Pol I effectively blocks the growth of prostate cancer cells. Silencing of p53, a pathway activated downstream of Pol I, does not diminish this effect. We find that BMH-21 significantly inhibited tumor growth and reduced the Ki67 proliferation index in an enzalutamide-resistant xenograft tumor model. A decrease in 45S rRNA synthesis demonstrated on-target activity. Furthermore, the Pol I inhibitor significantly inhibited tumor growth and pathology in an aggressive genetically modified Hoxb13-MYC|Hoxb13-Cre|Ptenfl/fl (BMPC) mouse prostate cancer model.CONCLUSION:
Taken together, BMH-21 is a novel promising molecule for the treatment of castration-resistant prostate cancer.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Próstata
/
RNA Polimerase I
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Neoplasias de Próstata Resistentes à Castração
/
Compostos Heterocíclicos de 4 ou mais Anéis
Tipo de estudo:
Clinical_trials
Limite:
Animals
/
Humans
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Male
Idioma:
En
Revista:
Prostate
Ano de publicação:
2019
Tipo de documento:
Article