Targeting the lysosome by an aminomethylated Riccardin D triggers DNA damage through cathepsin B-mediated degradation of BRCA1.
J Cell Mol Med
; 23(3): 1798-1812, 2019 03.
Article
em En
| MEDLINE
| ID: mdl-30565390
ABSTRACT
RD-N, an aminomethylated derivative of riccardin D, is a lysosomotropic agent that can trigger lysosomal membrane permeabilization followed by cathepsin B (CTSB)-dependent apoptosis in prostate cancer (PCa) cells, but the underlying mechanisms remain unknown. Here we show that RD-N treatment drives CTSB translocation from the lysosomes to the nucleus where it promotes DNA damage by suppression of the breast cancer 1 protein (BRCA1). Inhibition of CTSB activity with its specific inhibitors, or by CTSB-targeting siRNA or CTSB with enzyme-negative domain attenuated activation of BRCA1 and DNA damage induced by RD-N. Conversely, CTSB overexpression resulted in inhibition of BRCA1 and sensitized PCa cells to RD-N-induced cell death. Furthermore, RD-N-induced cell death was exacerbated in BRCA1-deficient cancer cells. We also demonstrated that CTSB/BRCA1-dependent DNA damage was critical for RD-N, but not for etoposide, reinforcing the importance of CTSB/BRCA1 in RD-N-mediated cell death. In addition, RD-N synergistically increased cell sensitivity to cisplatin, and this effect was more evidenced in BRCA1-deficient cancer cells. This study reveals a novel molecular mechanism that RD-N promotes CTSB-dependent DNA damage by the suppression of BRCA1 in PCa cells, leading to the identification of a potential compound that target lysosomes for cancer treatment.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Éteres Fenílicos
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Neoplasias da Próstata
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Estilbenos
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Dano ao DNA
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Catepsina B
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Proteína BRCA1
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Aminas
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Lisossomos
Limite:
Humans
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Male
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article