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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: Babagana, Mahamat, Brown, Lorin R., Slabodkin, Hannah Z., Kichina, Julia V., Kandel, Eugene S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8583472/
https://www.ncbi.nlm.nih.gov/pubmed/34768807
http://dx.doi.org/10.3390/ijms222111376
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author Babagana, Mahamat
Brown, Lorin R.
Slabodkin, Hannah Z.
Kichina, Julia V.
Kandel, Eugene S.
author_facet Babagana, Mahamat
Brown, Lorin R.
Slabodkin, Hannah Z.
Kichina, Julia V.
Kandel, Eugene S.
author_sort Babagana, Mahamat
collection PubMed
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.
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spelling pubmed-85834722021-11-12 Proteotoxic Stress as an Exploitable Vulnerability in Cells with Hyperactive AKT Babagana, Mahamat Brown, Lorin R. Slabodkin, Hannah Z. Kichina, Julia V. Kandel, Eugene S. Int J Mol Sci Article 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. MDPI 2021-10-21 /pmc/articles/PMC8583472/ /pubmed/34768807 http://dx.doi.org/10.3390/ijms222111376 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Babagana, Mahamat
Brown, Lorin R.
Slabodkin, Hannah Z.
Kichina, Julia V.
Kandel, Eugene S.
Proteotoxic Stress as an Exploitable Vulnerability in Cells with Hyperactive AKT
title 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_short Proteotoxic Stress as an Exploitable Vulnerability in Cells with Hyperactive AKT
title_sort proteotoxic stress as an exploitable vulnerability in cells with hyperactive akt
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8583472/
https://www.ncbi.nlm.nih.gov/pubmed/34768807
http://dx.doi.org/10.3390/ijms222111376
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