Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Nogueira, Veronique, Patra, Krushna C, Hay, Nissim
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2018
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
_version_ 1783327851024482304
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
work_keys_str_mv AT nogueiraveronique selectiveeradicationofcancerdisplayinghyperactiveaktbyexploitingthemetabolicconsequencesofaktactivation
AT patrakrushnac selectiveeradicationofcancerdisplayinghyperactiveaktbyexploitingthemetabolicconsequencesofaktactivation
AT haynissim selectiveeradicationofcancerdisplayinghyperactiveaktbyexploitingthemetabolicconsequencesofaktactivation