High-content, high-throughput analysis of cell cycle perturbations induced by the HSP90 inhibitor XL888.

<h4>Background</h4>Many proteins that are dysregulated or mutated in cancer cells rely on the molecular chaperone HSP90 for their proper folding and activity, which has led to considerable interest in HSP90 as a cancer drug target. The diverse array of HSP90 client proteins encompasses o...

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Autores principales:	Susan K Lyman, Suzanne C Crawley, Ruoyu Gong, Joanne I Adamkewicz, Garth McGrath, Jason Y Chew, Jennifer Choi, Charles R Holst, Leanne H Goon, Scott A Detmer, Jana Vaclavikova, Mary E Gerritsen, Robert A Blake
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f3255661be8a49999d93ff431dca0903
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spelling	oai:doaj.org-article:f3255661be8a49999d93ff431dca09032021-11-18T06:57:43ZHigh-content, high-throughput analysis of cell cycle perturbations induced by the HSP90 inhibitor XL888.1932-620310.1371/journal.pone.0017692https://doaj.org/article/f3255661be8a49999d93ff431dca09032011-03-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21408192/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Many proteins that are dysregulated or mutated in cancer cells rely on the molecular chaperone HSP90 for their proper folding and activity, which has led to considerable interest in HSP90 as a cancer drug target. The diverse array of HSP90 client proteins encompasses oncogenic drivers, cell cycle components, and a variety of regulatory factors, so inhibition of HSP90 perturbs multiple cellular processes, including mitogenic signaling and cell cycle control. Although many reports have investigated HSP90 inhibition in the context of the cell cycle, no large-scale studies have examined potential correlations between cell genotype and the cell cycle phenotypes of HSP90 inhibition.<h4>Methodology/principal findings</h4>To address this question, we developed a novel high-content, high-throughput cell cycle assay and profiled the effects of two distinct small molecule HSP90 inhibitors (XL888 and 17-AAG [17-allylamino-17-demethoxygeldanamycin]) in a large, genetically diverse panel of cancer cell lines. The cell cycle phenotypes of both inhibitors were strikingly similar and fell into three classes: accumulation in M-phase, G2-phase, or G1-phase. Accumulation in M-phase was the most prominent phenotype and notably, was also correlated with TP53 mutant status. We additionally observed unexpected complexity in the response of the cell cycle-associated client PLK1 to HSP90 inhibition, and we suggest that inhibitor-induced PLK1 depletion may contribute to the striking metaphase arrest phenotype seen in many of the M-arrested cell lines.<h4>Conclusions/significance</h4>Our analysis of the cell cycle phenotypes induced by HSP90 inhibition in 25 cancer cell lines revealed that the phenotypic response was highly dependent on cellular genotype as well as on the concentration of HSP90 inhibitor and the time of treatment. M-phase arrest correlated with the presence of TP53 mutations, while G2 or G1 arrest was more commonly seen in cells bearing wt TP53. We draw upon previous literature to suggest an integrated model that accounts for these varying observations.Susan K LymanSuzanne C CrawleyRuoyu GongJoanne I AdamkewiczGarth McGrathJason Y ChewJennifer ChoiCharles R HolstLeanne H GoonScott A DetmerJana VaclavikovaMary E GerritsenRobert A BlakePublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 3, p e17692 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Susan K Lyman Suzanne C Crawley Ruoyu Gong Joanne I Adamkewicz Garth McGrath Jason Y Chew Jennifer Choi Charles R Holst Leanne H Goon Scott A Detmer Jana Vaclavikova Mary E Gerritsen Robert A Blake High-content, high-throughput analysis of cell cycle perturbations induced by the HSP90 inhibitor XL888.
description	<h4>Background</h4>Many proteins that are dysregulated or mutated in cancer cells rely on the molecular chaperone HSP90 for their proper folding and activity, which has led to considerable interest in HSP90 as a cancer drug target. The diverse array of HSP90 client proteins encompasses oncogenic drivers, cell cycle components, and a variety of regulatory factors, so inhibition of HSP90 perturbs multiple cellular processes, including mitogenic signaling and cell cycle control. Although many reports have investigated HSP90 inhibition in the context of the cell cycle, no large-scale studies have examined potential correlations between cell genotype and the cell cycle phenotypes of HSP90 inhibition.<h4>Methodology/principal findings</h4>To address this question, we developed a novel high-content, high-throughput cell cycle assay and profiled the effects of two distinct small molecule HSP90 inhibitors (XL888 and 17-AAG [17-allylamino-17-demethoxygeldanamycin]) in a large, genetically diverse panel of cancer cell lines. The cell cycle phenotypes of both inhibitors were strikingly similar and fell into three classes: accumulation in M-phase, G2-phase, or G1-phase. Accumulation in M-phase was the most prominent phenotype and notably, was also correlated with TP53 mutant status. We additionally observed unexpected complexity in the response of the cell cycle-associated client PLK1 to HSP90 inhibition, and we suggest that inhibitor-induced PLK1 depletion may contribute to the striking metaphase arrest phenotype seen in many of the M-arrested cell lines.<h4>Conclusions/significance</h4>Our analysis of the cell cycle phenotypes induced by HSP90 inhibition in 25 cancer cell lines revealed that the phenotypic response was highly dependent on cellular genotype as well as on the concentration of HSP90 inhibitor and the time of treatment. M-phase arrest correlated with the presence of TP53 mutations, while G2 or G1 arrest was more commonly seen in cells bearing wt TP53. We draw upon previous literature to suggest an integrated model that accounts for these varying observations.
format	article
author	Susan K Lyman Suzanne C Crawley Ruoyu Gong Joanne I Adamkewicz Garth McGrath Jason Y Chew Jennifer Choi Charles R Holst Leanne H Goon Scott A Detmer Jana Vaclavikova Mary E Gerritsen Robert A Blake
author_facet	Susan K Lyman Suzanne C Crawley Ruoyu Gong Joanne I Adamkewicz Garth McGrath Jason Y Chew Jennifer Choi Charles R Holst Leanne H Goon Scott A Detmer Jana Vaclavikova Mary E Gerritsen Robert A Blake
author_sort	Susan K Lyman
title	High-content, high-throughput analysis of cell cycle perturbations induced by the HSP90 inhibitor XL888.
title_short	High-content, high-throughput analysis of cell cycle perturbations induced by the HSP90 inhibitor XL888.
title_full	High-content, high-throughput analysis of cell cycle perturbations induced by the HSP90 inhibitor XL888.
title_fullStr	High-content, high-throughput analysis of cell cycle perturbations induced by the HSP90 inhibitor XL888.
title_full_unstemmed	High-content, high-throughput analysis of cell cycle perturbations induced by the HSP90 inhibitor XL888.
title_sort	high-content, high-throughput analysis of cell cycle perturbations induced by the hsp90 inhibitor xl888.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/f3255661be8a49999d93ff431dca0903
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High-content, high-throughput analysis of cell cycle perturbations induced by the HSP90 inhibitor XL888.

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