title: 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 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.
authors.affiliation: The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Nader
authors.initials: N
authors.lastname: Al Nakouzi
authors.affiliation: The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Chris Kedong
authors.initials: CK
authors.lastname: Wang
authors.affiliation: The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Eliana
authors.initials: E
authors.lastname: Beraldi
authors.affiliation: The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Jager
authors.affiliation: The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Susan
authors.initials: S
authors.lastname: Ettinger
authors.affiliation: The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Ladan
authors.initials: L
authors.lastname: Fazli
authors.affiliation: The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Lucia
authors.initials: L
authors.lastname: Nappi
authors.affiliation: The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Bishop
authors.affiliation: The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Cancer Medicine, Gustave Roussy, Cancer Campus, Grand Paris, University of Paris-Sud, Villejuif, France INSERM U981, Villejuif, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Chauchereau
authors.affiliation: Department of Cancer Medicine, Gustave Roussy, Cancer Campus, Grand Paris, University of Paris-Sud, Villejuif, France INSERM U981, Villejuif, France.
authors.forename: Yohann
authors.initials: Y
authors.lastname: Loriot
authors.affiliation: The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada m.gleave@ubc.ca.
authors.forename: Martin
authors.identifier: 0000-0003-4235-0167
authors.initials: M
authors.lastname: Gleave
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D051152:Clusterin / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D008938:Mitosis / Q000187:drug effects*; D011471:Prostatic Neoplasms / Q000473:pathology*; D043823:Taxoids / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; D051152:Clusterin; D043823:Taxoids; C080625:taxane
keywords: Cdc25C; Wee1; cabazitaxel; clusterin; mitotic exit