Dual role of Par-4 in abrogation of EMT and switching on Mesenchymal to Epithelial Transition (MET) in metastatic pancreatic cancer cells.
Mol Carcinog
; 57(9): 1102-1115, 2018 09.
Article
em En
| MEDLINE
| ID: mdl-29672923
ABSTRACT
Epithelial-mesenchymal transition (EMT) is a critical event that occurs during the invasion and metastatic spread of cancer cells. Here, we conceive a dual mechanism of Par-4-mediated inhibition of EMT and induction of MET in metastatic pancreatic cancer cells. First, we demonstrate that 1,1'-ß-D-glucopyranosyl-3,3'-bis(5-bromoindolyl)-octyl methane (NGD16), an N-glycosylated derivative of medicinally important phytochemical 3,3'-diindolylmethane (DIM) abrogates EMT by inducing pro-apoptotic protein Par-4. Induction of Par-4 (by NGD16 or ectopic overexpression) strongly impedes invasion with inhibition of major mesenchymal markers viz. Vimentin and Twist-1 epithelial marker- E-cadherin. Further, NGD16 triggers MET phenotypes in pancreatic cancer cells by augmenting ALK2/Smad4 signaling in a Par-4-dependent manner. Conversely, siRNA-mediated silencing of endogenous Par-4 unveil reversal of MET with diminished E-cadherin expression and invasive phenotypes. Additionally, we demonstrate that intact Smad4 is essential for Par-4-mediated maintenance of E-cadherin level in MET induced cells. Notably, we imply that Par-4 induction regulates E-cadherin levels in the pancreatic cancer cells via modulating Twist-1 promoter activity. Finally, in vivo studies with syngenic mouse metastatic pancreatic cancer model reveal that NGD16 strongly suppresses metastatic burden, ascites formation, and prolongs the overall survival of animals effectively.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Pancreáticas
/
Regulação Neoplásica da Expressão Gênica
/
Proteínas Reguladoras de Apoptose
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Transição Epitelial-Mesenquimal
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Invasividade Neoplásica
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Mol Carcinog
Assunto da revista:
BIOLOGIA MOLECULAR
/
NEOPLASIAS
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Índia