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.
EMBO molecular medicine. 2016 May 19 [Epub ahead of print]
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
The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada., The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada., The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada., The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada., The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada., The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada., The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada., The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada., The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada., Department of Cancer Medicine, Gustave Roussy, Cancer Campus, Grand Paris, University of Paris-Sud, Villejuif, France INSERM U981, Villejuif, France., Department of Cancer Medicine, Gustave Roussy, Cancer Campus, Grand Paris, University of Paris-Sud, Villejuif, France INSERM U981, Villejuif, France., The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada .