| Autor: |
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 |
| Jazyk: |
angličtina |
| Rok vydání: |
2018 |
| Předmět: |
|
| Zdroj: |
Cell Reports, Vol 23, Iss 1, Pp 58-67 (2018) |
| Druh dokumentu: |
article |
| ISSN: |
2211-1247 |
| DOI: |
10.1016/j.celrep.2018.03.032 |
| Popis: |
Summary: 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. Keywords: Pten, mitochondria, deguelin, prostate cancer, complex I, ATP synthase, metabolism, glucose, RapidCaP, ATP |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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