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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 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.

SUBMITTER: Naguib A

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

REPOSITORIES: biostudies-literature

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

Naguib Adam A Mathew Grinu G Reczek Colleen R CR Watrud Kaitlin K Ambrico Alexandra A Herzka Tali T Salas Irene Casanova IC Lee Matthew F MF El-Amine Nour N Zheng Wu W Di Francesco M Emilia ME Marszalek Joseph R JR Pappin Darryl J DJ Chandel Navdeep S NS Trotman Lloyd C LC

Cell reports 20180401 1

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<sup>-/-</sup>;Trp53<sup>-/-</sup> 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 ...[more]

PMID: 29617673

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Project description:BACKGROUND:Numerous recent studies have shown that resident symbiotic microorganisms of insects play a fundamental role in host ecology and evolution. The lepidopteran pest, African armyworm (Spodoptera exempta), is a highly migratory and destructive species found throughout sub-Saharan Africa, that can experience eruptive outbreaks within the space of a single generation, making predicting population dynamics and pest control forecasting extremely difficult. Three strains of Wolbachia have recently been identified infecting this species in populations sampled from Tanzania. In this study, we examined the interaction between Wolbachia pipiensis infections and the co-inherited marker, mtDNA, within populations of armyworm, as a means to investigate the population biology and evolutionary history of Wolbachia and its host. RESULTS:A Wolbachia-infected isofemale line was established in the laboratory. Phenotypic studies confirmed the strain wExe1 as a male-killer. Partial sequencing of the mitochondrial COI gene from 164 individual field-collected armyworm of known infection status revealed 17 different haplotypes. There was a strong association between Wolbachia infection status and mtDNA haplotype, with a single dominant haplotype, haplo1 (90.2% prevalence), harbouring the endosymbiont. All three Wolbachia strains were associated with this haplotype. This indicates that Wolbachia may be driving a selective sweep on armyworm haplotype diversity. Despite very strong biological and molecular evidence that the samples represent a single species (including from nuclear 28S gene markers), the 17 haplotypes did not fall into a monophyletic clade within the Spodoptera genus; with six haplotypes (2 each from 3 geographically separate populations) differing by >11% in their nucleotide sequence to the other eleven. CONCLUSIONS:This study suggests that three strains of Wolbachia may be driving a selective sweep on armyworm haplotype diversity, and that based on COI sequence data, S. exempta is not a monophyletic group within the Spodoptera genus. This has clear implications for the use of mtDNA as neutral genetic markers in insects, and also demonstrates the impact of Wolbachia infections on host evolutionary genetics.

Dataset Information

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

Publications

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

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