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Cell Rep. 2018 Apr 3;23(1):58-67. doi: 10.1016/j.celrep.2018.03.032.

Mitochondrial Complex I Inhibitors Expose a Vulnerability for Selective Killing of Pten-Null Cells.

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Cold Spring Harbor Laboratory, Cancer Biology, Cold Spring Harbor, NY, USA.
Northwestern Medical School, Cell and Molecular Biology, Chicago, IL, USA.
Institute for Applied Cancer Science, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
Cold Spring Harbor Laboratory, Cancer Biology, Cold Spring Harbor, NY, USA. Electronic address:


A hallmark of advanced prostate cancer (PC) is the concomitant loss of PTEN and p53 function. To selectively eliminate such cells, we screened cytotoxic compounds on Pten-/-;Trp53-/- fibroblasts and their Pten-WT reference. Highly selective killing of Pten-null cells can be achieved by deguelin, a natural insecticide. Deguelin eliminates Pten-deficient cells through inhibition of mitochondrial complex I (CI). Five hundred-fold higher drug doses are needed to obtain the same killing of Pten-WT cells, even though deguelin blocks their electron transport chain equally well. Selectivity arises because mitochondria of Pten-null cells consume ATP through complex V, instead of producing it. The resulting glucose dependency can be exploited to selectively kill Pten-null cells with clinically relevant CI inhibitors, especially if they are lipophilic. In vivo, deguelin suppressed disease in our genetically engineered mouse model for metastatic PC. Our data thus introduce a vulnerability for highly selective targeting of incurable PC with inhibitors of CI.


ATP; ATP synthase; Pten; RapidCaP; complex I; deguelin; glucose; metabolism; mitochondria; prostate cancer

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