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Clusterin knockdown sensitizes prostate cancer cells to taxane by modulating mitosis

Clusterin (CLU) is a stress‐activated molecular chaperone that confers treatment resistance to taxanes when highly expressed. While CLU inhibition potentiates activity of taxanes and other anti‐cancer therapies in preclinical models, progression to treatment‐resistant disease still occurs implicatin...

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Autores principales: Al Nakouzi, Nader, Wang, Chris Kedong, Beraldi, Eliana, Jager, Wolfgang, Ettinger, Susan, Fazli, Ladan, Nappi, Lucia, Bishop, Jennifer, Zhang, Fan, Chauchereau, Anne, Loriot, Yohann, Gleave, Martin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4931290/
https://www.ncbi.nlm.nih.gov/pubmed/27198502
http://dx.doi.org/10.15252/emmm.201506059
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author Al Nakouzi, Nader
Wang, Chris Kedong
Beraldi, Eliana
Jager, Wolfgang
Ettinger, Susan
Fazli, Ladan
Nappi, Lucia
Bishop, Jennifer
Zhang, Fan
Chauchereau, Anne
Loriot, Yohann
Gleave, Martin
author_facet Al Nakouzi, Nader
Wang, Chris Kedong
Beraldi, Eliana
Jager, Wolfgang
Ettinger, Susan
Fazli, Ladan
Nappi, Lucia
Bishop, Jennifer
Zhang, Fan
Chauchereau, Anne
Loriot, Yohann
Gleave, Martin
author_sort Al Nakouzi, Nader
collection PubMed
description Clusterin (CLU) is a stress‐activated molecular chaperone that confers treatment resistance to taxanes when highly expressed. While CLU inhibition potentiates activity of taxanes and other anti‐cancer therapies in preclinical models, progression to treatment‐resistant disease still occurs implicating additional compensatory survival mechanisms. Taxanes are believed to selectively target cells in mitosis, a complex mechanism controlled in part by balancing antagonistic roles of Cdc25C and Wee1 in mitosis progression. Our data indicate that CLU silencing induces a constitutive activation of Cdc25C, which delays mitotic exit and hence sensitizes cancer cells to mitotic‐targeting agents such as taxanes. Unchecked Cdc25C activation leads to mitotic catastrophe and cell death unless cells up‐regulate protective mechanisms mediated through the cell cycle regulators Wee1 and Cdk1. In this study, we show that CLU silencing induces a constitutive activation of Cdc25C via the phosphatase PP2A leading to relief of negative feedback inhibition and activation of Wee1‐Cdk1 to promote survival and limit therapeutic efficacy. Simultaneous inhibition of CLU‐regulated cell cycle effector Wee1 may improve synergistic responses of biologically rational combinatorial regimens using taxanes and CLU inhibitors.
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spelling pubmed-49312902016-07-08 Clusterin knockdown sensitizes prostate cancer cells to taxane by modulating mitosis Al Nakouzi, Nader Wang, Chris Kedong Beraldi, Eliana Jager, Wolfgang Ettinger, Susan Fazli, Ladan Nappi, Lucia Bishop, Jennifer Zhang, Fan Chauchereau, Anne Loriot, Yohann Gleave, Martin EMBO Mol Med Research Articles Clusterin (CLU) is a stress‐activated molecular chaperone that confers treatment resistance to taxanes when highly expressed. While CLU inhibition potentiates activity of taxanes and other anti‐cancer therapies in preclinical models, progression to treatment‐resistant disease still occurs implicating additional compensatory survival mechanisms. Taxanes are believed to selectively target cells in mitosis, a complex mechanism controlled in part by balancing antagonistic roles of Cdc25C and Wee1 in mitosis progression. Our data indicate that CLU silencing induces a constitutive activation of Cdc25C, which delays mitotic exit and hence sensitizes cancer cells to mitotic‐targeting agents such as taxanes. Unchecked Cdc25C activation leads to mitotic catastrophe and cell death unless cells up‐regulate protective mechanisms mediated through the cell cycle regulators Wee1 and Cdk1. In this study, we show that CLU silencing induces a constitutive activation of Cdc25C via the phosphatase PP2A leading to relief of negative feedback inhibition and activation of Wee1‐Cdk1 to promote survival and limit therapeutic efficacy. Simultaneous inhibition of CLU‐regulated cell cycle effector Wee1 may improve synergistic responses of biologically rational combinatorial regimens using taxanes and CLU inhibitors. John Wiley and Sons Inc. 2016-05-19 2016-07 /pmc/articles/PMC4931290/ /pubmed/27198502 http://dx.doi.org/10.15252/emmm.201506059 Text en © 2016 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the Creative Commons Attribution 4.0 (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Al Nakouzi, Nader
Wang, Chris Kedong
Beraldi, Eliana
Jager, Wolfgang
Ettinger, Susan
Fazli, Ladan
Nappi, Lucia
Bishop, Jennifer
Zhang, Fan
Chauchereau, Anne
Loriot, Yohann
Gleave, Martin
Clusterin knockdown sensitizes prostate cancer cells to taxane by modulating mitosis
title Clusterin knockdown sensitizes prostate cancer cells to taxane by modulating mitosis
title_full Clusterin knockdown sensitizes prostate cancer cells to taxane by modulating mitosis
title_fullStr Clusterin knockdown sensitizes prostate cancer cells to taxane by modulating mitosis
title_full_unstemmed Clusterin knockdown sensitizes prostate cancer cells to taxane by modulating mitosis
title_short Clusterin knockdown sensitizes prostate cancer cells to taxane by modulating mitosis
title_sort clusterin knockdown sensitizes prostate cancer cells to taxane by modulating mitosis
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4931290/
https://www.ncbi.nlm.nih.gov/pubmed/27198502
http://dx.doi.org/10.15252/emmm.201506059
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