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Selective eradication of cancer displaying hyperactive Akt by exploiting the metabolic consequences of Akt activation
Akt activation in human cancers exerts chemoresistance, but pan-Akt inhibition elicits adverse consequences. We exploited the consequences of Akt-mediated mitochondrial and glucose metabolism to selectively eradicate and evade chemoresistance of prostate cancer displaying hyperactive Akt. PTEN-defic...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980228/ https://www.ncbi.nlm.nih.gov/pubmed/29687779 http://dx.doi.org/10.7554/eLife.32213 |
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author | Nogueira, Veronique Patra, Krushna C Hay, Nissim |
author_facet | Nogueira, Veronique Patra, Krushna C Hay, Nissim |
author_sort | Nogueira, Veronique |
collection | PubMed |
description | Akt activation in human cancers exerts chemoresistance, but pan-Akt inhibition elicits adverse consequences. We exploited the consequences of Akt-mediated mitochondrial and glucose metabolism to selectively eradicate and evade chemoresistance of prostate cancer displaying hyperactive Akt. PTEN-deficient prostate cancer cells that display hyperactivated Akt have high intracellular reactive oxygen species (ROS) levels, in part, because of Akt-dependent increase of oxidative phosphorylation. High intracellular ROS levels selectively sensitize cells displaying hyperactive Akt to ROS-induced cell death enabling a therapeutic strategy combining a ROS inducer and rapamycin in PTEN-deficient prostate tumors in mouse models. This strategy elicited tumor regression, and markedly increased survival even after the treatment was stopped. By contrast, exposure to antioxidant increased prostate tumor progression. To increase glucose metabolism, Akt activation phosphorylated HK2 and induced its expression. Indeed, HK2 deficiency in mouse models of Pten-deficient prostate cancer elicited a marked inhibition of tumor development and extended lifespan. |
format | Online Article Text |
id | pubmed-5980228 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-59802282018-06-04 Selective eradication of cancer displaying hyperactive Akt by exploiting the metabolic consequences of Akt activation Nogueira, Veronique Patra, Krushna C Hay, Nissim eLife Cancer Biology Akt activation in human cancers exerts chemoresistance, but pan-Akt inhibition elicits adverse consequences. We exploited the consequences of Akt-mediated mitochondrial and glucose metabolism to selectively eradicate and evade chemoresistance of prostate cancer displaying hyperactive Akt. PTEN-deficient prostate cancer cells that display hyperactivated Akt have high intracellular reactive oxygen species (ROS) levels, in part, because of Akt-dependent increase of oxidative phosphorylation. High intracellular ROS levels selectively sensitize cells displaying hyperactive Akt to ROS-induced cell death enabling a therapeutic strategy combining a ROS inducer and rapamycin in PTEN-deficient prostate tumors in mouse models. This strategy elicited tumor regression, and markedly increased survival even after the treatment was stopped. By contrast, exposure to antioxidant increased prostate tumor progression. To increase glucose metabolism, Akt activation phosphorylated HK2 and induced its expression. Indeed, HK2 deficiency in mouse models of Pten-deficient prostate cancer elicited a marked inhibition of tumor development and extended lifespan. eLife Sciences Publications, Ltd 2018-04-24 /pmc/articles/PMC5980228/ /pubmed/29687779 http://dx.doi.org/10.7554/eLife.32213 Text en © 2018, Nogueira et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Cancer Biology Nogueira, Veronique Patra, Krushna C Hay, Nissim Selective eradication of cancer displaying hyperactive Akt by exploiting the metabolic consequences of Akt activation |
title | Selective eradication of cancer displaying hyperactive Akt by exploiting the metabolic consequences of Akt activation |
title_full | Selective eradication of cancer displaying hyperactive Akt by exploiting the metabolic consequences of Akt activation |
title_fullStr | Selective eradication of cancer displaying hyperactive Akt by exploiting the metabolic consequences of Akt activation |
title_full_unstemmed | Selective eradication of cancer displaying hyperactive Akt by exploiting the metabolic consequences of Akt activation |
title_short | Selective eradication of cancer displaying hyperactive Akt by exploiting the metabolic consequences of Akt activation |
title_sort | selective eradication of cancer displaying hyperactive akt by exploiting the metabolic consequences of akt activation |
topic | Cancer Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980228/ https://www.ncbi.nlm.nih.gov/pubmed/29687779 http://dx.doi.org/10.7554/eLife.32213 |
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