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)
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 School of Biological Sciences > Publications CSHL Cancer Center Program > Cellular Communication in Cancer Program |
| Depositing User: | Matt Covey |
| Date: | 3 April 2018 |
| Date Deposited: | 06 Apr 2018 14:54 |
| Last Modified: | 14 Dec 2020 17:08 |
| PMCID: | PMC6003704 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/36346 |
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