The metastasis suppressor, NDRG1, attenuates oncogenic TGF-ß and NF-κB signaling to enhance membrane E-cadherin expression in pancreatic cancer cells.
Carcinogenesis
; 40(6): 805-818, 2019 07 06.
Article
em En
| MEDLINE
| ID: mdl-30561520
ABSTRACT
The metastasis suppressor, N-myc downstream-regulated gene-1 (NDRG1), plays multifaceted roles in inhibiting oncogenic signaling and can suppress the epithelial mesenchymal transition (EMT), a key step in metastasis. In this investigation, NDRG1 inhibited the oncogenic effects of transforming growth factor-ß (TGF-ß) in PANC-1 pancreatic cancer cells, promoting expression and co-localization of E-cadherin and ß-catenin at the cell membrane. A similar effect of NDRG1 at supporting E-cadherin and ß-catenin co-localization at the cell membrane was also demonstrated for HT-29 colon and CFPAC-1 pancreatic cancer cells. The increase in E-cadherin in PANC-1 cells in response to NDRG1 was mediated by the reduction of three transcriptional repressors of E-cadherin, namely SNAIL, SLUG and ZEB1. To dissect the mechanisms how NDRG1 inhibits nuclear SNAIL, SLUG and ZEB1, we assessed involvement of the nuclear factor-κB (NF-κB) pathway, as its aberrant activation contributes to the EMT. Interestingly, NDRG1 comprehensively inhibited oncogenic NF-κB signaling at multiple sites in this pathway, suppressing NEMO, Iĸĸα and IĸBα expression, as well as reducing the activating phosphorylation of Iĸĸα/ß and IĸBα. NDRG1 also reduced the levels, nuclear co-localization and DNA-binding activity of NF-κB p65. Further, Iĸĸα, which integrates NF-κB and TGF-ß signaling to upregulate ZEB1, SNAIL and SLUG, was identified as an NDRG1 target. Considering this, therapies targeting NDRG1 could be a new strategy to inhibit metastasis, and as such, we examined novel anticancer agents, namely di-2-pyridylketone thiosemicarbazones, which upregulate NDRG1. These agents downregulated SNAIL, SLUG and ZEB1 in vitro and in vivo using a PANC-1 tumor xenograft model, demonstrating their marked potential.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Pancreáticas
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Transdução de Sinais
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Antígenos CD
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Caderinas
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NF-kappa B
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Fator de Crescimento Transformador beta
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Proteínas de Ciclo Celular
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Peptídeos e Proteínas de Sinalização Intracelular
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Metástase Neoplásica
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Carcinogenesis
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Austrália