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PI3K/AKT pathway regulates E-cadherin and Desmoglein 2 in aggressive prostate cancer
Reduced expression of both classical and desmosomal cadherins has been associated with different types of carcinomas, including prostate cancer. This study aims to provide a comprehensive view of the role and regulation of cell–cell adhesion in prostate cancer aggressiveness by examining the functio...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley & Sons, Ltd
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4559037/ https://www.ncbi.nlm.nih.gov/pubmed/26033689 http://dx.doi.org/10.1002/cam4.463 |
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author | Barber, Alison G Castillo-Martin, Mireia Bonal, Dennis M Jia, Angela J Rybicki, Benjamin A Christiano, Angela M Cordon-Cardo, Carlos |
author_facet | Barber, Alison G Castillo-Martin, Mireia Bonal, Dennis M Jia, Angela J Rybicki, Benjamin A Christiano, Angela M Cordon-Cardo, Carlos |
author_sort | Barber, Alison G |
collection | PubMed |
description | Reduced expression of both classical and desmosomal cadherins has been associated with different types of carcinomas, including prostate cancer. This study aims to provide a comprehensive view of the role and regulation of cell–cell adhesion in prostate cancer aggressiveness by examining the functional implications of both E-cadherin and Desmoglein 2 (DSG2). E-cadherin expression was first examined using immunofluorescence in 50 normal prostate tissues and in a cohort of 414 prostate cancer patients. Correlation and survival analyses were performed to assess its clinical significance. In primary prostate cancer patients, reduced expression of both E-cadherin and DSG2 is significantly associated with an earlier biochemical recurrence. Transgenic DU145 E-cadherin knockdown and constitutively active AKT overexpression lines were generated. Functional implications of such genetic alterations were analyzed in vitro and in vivo, the latter by using tumorigenesis as well as extravasation and metastatic tumor formation assays. We observed that loss of E-cadherin leads to impaired primary and metastatic tumor formation in vivo, suggesting a tumor promoter role for E-cadherin in addition to its known role as a tumor suppressor. Activation of AKT leads to a significant reduction in E-cadherin expression and nuclear localization of Snail, suggesting a role for the PI3K/AKT signaling pathway in the transient repression of E-cadherin. This reduced expression may be regulated by separate mechanisms as neither the loss of E-cadherin nor activation of AKT significantly affected DSG2 expression. In conclusion, these findings illustrate the critical role of cell–cell adhesion in the progression to aggressive prostate cancer, through regulation by the PI3K pathway. |
format | Online Article Text |
id | pubmed-4559037 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | John Wiley & Sons, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-45590372015-09-09 PI3K/AKT pathway regulates E-cadherin and Desmoglein 2 in aggressive prostate cancer Barber, Alison G Castillo-Martin, Mireia Bonal, Dennis M Jia, Angela J Rybicki, Benjamin A Christiano, Angela M Cordon-Cardo, Carlos Cancer Med Cancer Biology Reduced expression of both classical and desmosomal cadherins has been associated with different types of carcinomas, including prostate cancer. This study aims to provide a comprehensive view of the role and regulation of cell–cell adhesion in prostate cancer aggressiveness by examining the functional implications of both E-cadherin and Desmoglein 2 (DSG2). E-cadherin expression was first examined using immunofluorescence in 50 normal prostate tissues and in a cohort of 414 prostate cancer patients. Correlation and survival analyses were performed to assess its clinical significance. In primary prostate cancer patients, reduced expression of both E-cadherin and DSG2 is significantly associated with an earlier biochemical recurrence. Transgenic DU145 E-cadherin knockdown and constitutively active AKT overexpression lines were generated. Functional implications of such genetic alterations were analyzed in vitro and in vivo, the latter by using tumorigenesis as well as extravasation and metastatic tumor formation assays. We observed that loss of E-cadherin leads to impaired primary and metastatic tumor formation in vivo, suggesting a tumor promoter role for E-cadherin in addition to its known role as a tumor suppressor. Activation of AKT leads to a significant reduction in E-cadherin expression and nuclear localization of Snail, suggesting a role for the PI3K/AKT signaling pathway in the transient repression of E-cadherin. This reduced expression may be regulated by separate mechanisms as neither the loss of E-cadherin nor activation of AKT significantly affected DSG2 expression. In conclusion, these findings illustrate the critical role of cell–cell adhesion in the progression to aggressive prostate cancer, through regulation by the PI3K pathway. John Wiley & Sons, Ltd 2015-08 2015-05-29 /pmc/articles/PMC4559037/ /pubmed/26033689 http://dx.doi.org/10.1002/cam4.463 Text en © 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. http://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Cancer Biology Barber, Alison G Castillo-Martin, Mireia Bonal, Dennis M Jia, Angela J Rybicki, Benjamin A Christiano, Angela M Cordon-Cardo, Carlos PI3K/AKT pathway regulates E-cadherin and Desmoglein 2 in aggressive prostate cancer |
title | PI3K/AKT pathway regulates E-cadherin and Desmoglein 2 in aggressive prostate cancer |
title_full | PI3K/AKT pathway regulates E-cadherin and Desmoglein 2 in aggressive prostate cancer |
title_fullStr | PI3K/AKT pathway regulates E-cadherin and Desmoglein 2 in aggressive prostate cancer |
title_full_unstemmed | PI3K/AKT pathway regulates E-cadherin and Desmoglein 2 in aggressive prostate cancer |
title_short | PI3K/AKT pathway regulates E-cadherin and Desmoglein 2 in aggressive prostate cancer |
title_sort | pi3k/akt pathway regulates e-cadherin and desmoglein 2 in aggressive prostate cancer |
topic | Cancer Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4559037/ https://www.ncbi.nlm.nih.gov/pubmed/26033689 http://dx.doi.org/10.1002/cam4.463 |
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