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

Naguib, A., Mathew, G., Reczek, C. R., Watrud, K., Ambrico, A., Herzka, T., Salas, I. C., Lee, M. F., El-Amine, N., Zheng, W., Di Francesco, M. E., Marszalek, J. R., Pappin, D. J., Chandel, N. S., Trotman, L. C. (April 2018) Mitochondrial Complex I Inhibitors Expose a Vulnerability for Selective Killing of Pten-Null Cells. Cell Rep, 23 (1). pp. 58-67. ISSN 2211-1247 (Electronic)

URL: https://www.ncbi.nlm.nih.gov/pubmed/29617673
DOI: 10.1016/j.celrep.2018.03.032

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.

Item Type: Paper
Uncontrolled Keywords: Atp ATP synthase Pten RapidCaP complex I deguelin glucose metabolism mitochondria prostate cancer
Subjects: bioinformatics > genomics and proteomics > small molecules > ATP
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > PTEN
organs, tissues, organelles, cell types and functions > organelles, types and functions > mitochondria
diseases & disorders > cancer > cancer types > prostate cancer
CSHL Authors:
Communities: CSHL Cancer Center Program > Signal Transduction
CSHL labs > Pappin lab
CSHL labs > Trotman lab
Watson School > Publications
Depositing User: Matt Covey
Date: 3 April 2018
Date Deposited: 06 Apr 2018 14:54
Last Modified: 03 Jan 2019 21:32
Related URLs:
URI: http://repository.cshl.edu/id/eprint/36346

Actions (login required)

Administrator's edit/view item Administrator's edit/view item
CSHL HomeAbout CSHLResearchEducationNews & FeaturesCampus & Public EventsCareersGiving