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*

*Corresponding author for this work

Research output: Contribution to journalArticle

11 Scopus citations

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. 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.

Original languageEnglish (US)
Pages (from-to)58-67
Number of pages10
JournalCell reports
Volume23
Issue number1
DOIs
StatePublished - Apr 3 2018

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Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

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. (2018). Mitochondrial Complex I Inhibitors Expose a Vulnerability for Selective Killing of Pten-Null Cells. Cell reports, 23(1), 58-67. https://doi.org/10.1016/j.celrep.2018.03.032