Proteotoxic Stress as an Exploitable Vulnerability in Cells with Hyperactive AKT

Hyperactivity of serine-threonine kinase AKT is one of the most common molecular abnormalities in cancer, where it contributes to poor outcomes by facilitating the growth and survival of malignant cells. Despite its well-documented anti-apoptotic effects, hyperactivity of AKT is also known to be str...

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Autores principales:	Mahamat Babagana, Lorin R. Brown, Hannah Z. Slabodkin, Julia V. Kichina, Eugene S. Kandel
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	heat shock AKT PTEN XBP1 HSF1 HSP70 Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/8ae2ee8ed42540349ba0efdb1b430775
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spelling	oai:doaj.org-article:8ae2ee8ed42540349ba0efdb1b4307752021-11-11T16:50:59ZProteotoxic Stress as an Exploitable Vulnerability in Cells with Hyperactive AKT10.3390/ijms2221113761422-00671661-6596https://doaj.org/article/8ae2ee8ed42540349ba0efdb1b4307752021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11376https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Hyperactivity of serine-threonine kinase AKT is one of the most common molecular abnormalities in cancer, where it contributes to poor outcomes by facilitating the growth and survival of malignant cells. Despite its well-documented anti-apoptotic effects, hyperactivity of AKT is also known to be stressful to a cell. In an attempt to better elucidate this phenomenon, we observed the signs of proteotoxic stress in cells that harbor hyperactive AKT or have lost its principal negative regulator, PTEN. The activity of HSF1 was predictably elevated under these circumstances. However, such cells proved more sensitive to various regimens of heat shock, including the conditions that were well-tolerated by syngeneic cells without AKT hyperactivity. The sensitizing effect of hyperactive AKT was also seen in HSF1-deficient cells, suggesting that the phenomenon does not require the regulation of HSF1 by this kinase. Notably, the elevated activity of AKT was accompanied by increased levels of XBP1, a key component of cell defense against proteotoxic stress. Interestingly, the cells harboring hyperactive AKT were also more dependent on XBP1 for their growth. Our observations suggest that proteotoxic stress conferred by hyperactive AKT represents a targetable vulnerability, which can be exploited by either elevating the stress above the level tolerated by such cells or by eliminating the factors that enable such tolerance.Mahamat BabaganaLorin R. BrownHannah Z. SlabodkinJulia V. KichinaEugene S. KandelMDPI AGarticleheat shockAKTPTENXBP1HSF1HSP70Biology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11376, p 11376 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	heat shock AKT PTEN XBP1 HSF1 HSP70 Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	heat shock AKT PTEN XBP1 HSF1 HSP70 Biology (General) QH301-705.5 Chemistry QD1-999 Mahamat Babagana Lorin R. Brown Hannah Z. Slabodkin Julia V. Kichina Eugene S. Kandel Proteotoxic Stress as an Exploitable Vulnerability in Cells with Hyperactive AKT
description	Hyperactivity of serine-threonine kinase AKT is one of the most common molecular abnormalities in cancer, where it contributes to poor outcomes by facilitating the growth and survival of malignant cells. Despite its well-documented anti-apoptotic effects, hyperactivity of AKT is also known to be stressful to a cell. In an attempt to better elucidate this phenomenon, we observed the signs of proteotoxic stress in cells that harbor hyperactive AKT or have lost its principal negative regulator, PTEN. The activity of HSF1 was predictably elevated under these circumstances. However, such cells proved more sensitive to various regimens of heat shock, including the conditions that were well-tolerated by syngeneic cells without AKT hyperactivity. The sensitizing effect of hyperactive AKT was also seen in HSF1-deficient cells, suggesting that the phenomenon does not require the regulation of HSF1 by this kinase. Notably, the elevated activity of AKT was accompanied by increased levels of XBP1, a key component of cell defense against proteotoxic stress. Interestingly, the cells harboring hyperactive AKT were also more dependent on XBP1 for their growth. Our observations suggest that proteotoxic stress conferred by hyperactive AKT represents a targetable vulnerability, which can be exploited by either elevating the stress above the level tolerated by such cells or by eliminating the factors that enable such tolerance.
format	article
author	Mahamat Babagana Lorin R. Brown Hannah Z. Slabodkin Julia V. Kichina Eugene S. Kandel
author_facet	Mahamat Babagana Lorin R. Brown Hannah Z. Slabodkin Julia V. Kichina Eugene S. Kandel
author_sort	Mahamat Babagana
title	Proteotoxic Stress as an Exploitable Vulnerability in Cells with Hyperactive AKT
title_short	Proteotoxic Stress as an Exploitable Vulnerability in Cells with Hyperactive AKT
title_full	Proteotoxic Stress as an Exploitable Vulnerability in Cells with Hyperactive AKT
title_fullStr	Proteotoxic Stress as an Exploitable Vulnerability in Cells with Hyperactive AKT
title_full_unstemmed	Proteotoxic Stress as an Exploitable Vulnerability in Cells with Hyperactive AKT
title_sort	proteotoxic stress as an exploitable vulnerability in cells with hyperactive akt
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/8ae2ee8ed42540349ba0efdb1b430775
work_keys_str_mv	AT mahamatbabagana proteotoxicstressasanexploitablevulnerabilityincellswithhyperactiveakt AT lorinrbrown proteotoxicstressasanexploitablevulnerabilityincellswithhyperactiveakt AT hannahzslabodkin proteotoxicstressasanexploitablevulnerabilityincellswithhyperactiveakt AT juliavkichina proteotoxicstressasanexploitablevulnerabilityincellswithhyperactiveakt AT eugeneskandel proteotoxicstressasanexploitablevulnerabilityincellswithhyperactiveakt
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Proteotoxic Stress as an Exploitable Vulnerability in Cells with Hyperactive AKT

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