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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.

Author information

1
Cold Spring Harbor Laboratory, Cancer Biology, Cold Spring Harbor, NY, USA.
2
Northwestern Medical School, Cell and Molecular Biology, Chicago, IL, USA.
3
Institute for Applied Cancer Science, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
4
Cold Spring Harbor Laboratory, Cancer Biology, Cold Spring Harbor, NY, USA. Electronic address: trotman@cshl.edu.

Abstract

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.

KEYWORDS:

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

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