Clusterin knockdown sensitizes prostate cancer cells to taxane by modulating mitosis
Abstract 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 i...
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| Format: | Article |
| Language: | English |
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Springer Nature
2016-05-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201506059 |
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| author | Nader Al Nakouzi Chris Kedong Wang Eliana Beraldi Wolfgang Jager Susan Ettinger Ladan Fazli Lucia Nappi Jennifer Bishop Fan Zhang Anne Chauchereau Yohann Loriot Martin Gleave |
| author_facet | Nader Al Nakouzi Chris Kedong Wang Eliana Beraldi Wolfgang Jager Susan Ettinger Ladan Fazli Lucia Nappi Jennifer Bishop Fan Zhang Anne Chauchereau Yohann Loriot Martin Gleave |
| author_sort | Nader Al Nakouzi |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-ce8e9ec8a2684fddbbbf41bacd8abc50 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2016-05-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-ce8e9ec8a2684fddbbbf41bacd8abc502025-08-20T03:43:30ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842016-05-018776177810.15252/emmm.201506059Clusterin knockdown sensitizes prostate cancer cells to taxane by modulating mitosisNader Al Nakouzi0Chris Kedong Wang1Eliana Beraldi2Wolfgang Jager3Susan Ettinger4Ladan Fazli5Lucia Nappi6Jennifer Bishop7Fan Zhang8Anne Chauchereau9Yohann Loriot10Martin Gleave11The Vancouver Prostate Centre and Department of Urologic Sciences, University of British ColumbiaThe Vancouver Prostate Centre and Department of Urologic Sciences, University of British ColumbiaThe Vancouver Prostate Centre and Department of Urologic Sciences, University of British ColumbiaThe Vancouver Prostate Centre and Department of Urologic Sciences, University of British ColumbiaThe Vancouver Prostate Centre and Department of Urologic Sciences, University of British ColumbiaThe Vancouver Prostate Centre and Department of Urologic Sciences, University of British ColumbiaThe Vancouver Prostate Centre and Department of Urologic Sciences, University of British ColumbiaThe Vancouver Prostate Centre and Department of Urologic Sciences, University of British ColumbiaThe Vancouver Prostate Centre and Department of Urologic Sciences, University of British ColumbiaDepartment of Cancer Medicine, Gustave Roussy, Cancer Campus, Grand Paris, University of Paris‐SudDepartment of Cancer Medicine, Gustave Roussy, Cancer Campus, Grand Paris, University of Paris‐SudThe Vancouver Prostate Centre and Department of Urologic Sciences, University of British ColumbiaAbstract 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.https://doi.org/10.15252/emmm.201506059cabazitaxelCdc25Cclusterinmitotic exitWee1 |
| spellingShingle | Nader Al Nakouzi Chris Kedong Wang Eliana Beraldi Wolfgang Jager Susan Ettinger Ladan Fazli Lucia Nappi Jennifer Bishop Fan Zhang Anne Chauchereau Yohann Loriot Martin Gleave Clusterin knockdown sensitizes prostate cancer cells to taxane by modulating mitosis EMBO Molecular Medicine cabazitaxel Cdc25C clusterin mitotic exit Wee1 |
| 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 | cabazitaxel Cdc25C clusterin mitotic exit Wee1 |
| url | https://doi.org/10.15252/emmm.201506059 |
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