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

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

SUBMITTER: Naguib A 

PROVIDER: S-EPMC6003704 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature