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

Adam Naguib; Grinu Mathew; Colleen R. Reczek; Kaitlin Watrud; Alexandra Ambrico; Tali Herzka; Irene Casanova Salas; Matthew F. Lee; Nour El-Amine; Wu Zheng; M. Emilia Di Francesco; Joseph R. Marszalek; Darryl J. Pappin; Navdeep S. Chandel; Lloyd C. Trotman

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

2018

Summary: 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. : Naguib et al. find that Pten-null cells are highly vulnerable to mitochondrial complex I inhibition under conditions in which Pten-WT cells remain perfectly viable. They suggest that such an approach could serve as a blueprint for selective targeting of lethal Pten-deficient metastatic prostate cancer. Keywords: Pten, mitochondria, deguelin, prostate cancer, complex I, ATP synthase, metabolism, glucose, RapidCaP, ATP

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