Par-4 dependent modulation of cellular ß-catenin by medicinal plant natural product derivative 3-azido Withaferin A.
Mol Carcinog
; 55(5): 864-81, 2016 May.
Article
en En
| MEDLINE
| ID: mdl-25969134
ABSTRACT
Here, we provide evidences that natural product derivative 3-azido Withaferin A (3-AWA) abrogated EMT and invasion by modulating ß-catenin localization and its transcriptional activity in the prostate as well as in breast cancer cells. This study, for the first time, reveals 3-AWA treatment consistently sequestered nuclear ß-catenin and augmented its cytoplasmic pool as evidenced by reducing ß-catenin transcriptional activity in these cells. Moreover, 3-AWA treatment triggered robust induction of pro-apoptotic intracellular Par-4, attenuated Akt activity and rescued Phospho-GSK3ß (by Akt) to promote ß-catenin destabilization. Further, our in vitro studies demonstrate that 3-AWA treatment amplified E-cadherin expression along with sharp downregulation of c-Myc and cyclin D1 proteins. Strikingly, endogenous Par-4 knock down by siRNA underscored 3-AWA mediated inhibition of nuclear ß-catenin was Par-4 dependent and suppression of Par-4 activity, either by Bcl-2 or by Ras transfection, restored the nuclear ß-catenin level suggesting Par-4 mediated ß-catenin regulation was not promiscuous. In vivo results further demonstrated that 3-AWA was effective inhibitor of tumor growth and immunohistochemical studies indicated that increased expression of total ß-catenin and decreased expression of phospho-ß-catenin and Par-4 in breast cancer tissues as compared to normal breast tissue suggesting Par-4 and ß-catenin proteins are mutually regulated and inversely co-related in normal as well as cancer condition. Thus, strategic regulation of intracellular Par-4 by 3-AWA in diverse cancers could be an effective tool to control cancer cell metastasis. Conclusively, this report puts forward a novel approach of controlling deregulated ß-catenin signaling by 3-AWA induced Par-4 protein.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Proteínas Reguladoras de la Apoptosis
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Beta Catenina
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Witanólidos
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Neoplasias
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Antineoplásicos Fitogénicos
Límite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Mol Carcinog
Asunto de la revista:
BIOLOGIA MOLECULAR
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NEOPLASIAS
Año:
2016
Tipo del documento:
Article
País de afiliación:
India
Pais de publicación:
EEUU
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ESTADOS UNIDOS
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ESTADOS UNIDOS DA AMERICA
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EUA
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UNITED STATES
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UNITED STATES OF AMERICA
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US
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USA