High-content, high-throughput analysis of cell cycle perturbations induced by the HSP90 inhibitor XL888
| Autor: | Leanne H. Goon, Suzanne C. Crawley, Jana Vaclavikova, Joanne I. Adamkewicz, Garth Joseph Mcgrath, Scott A. Detmer, Robert A. Blake, Jason Y. Chew, Jennifer Choi, Susan K. Lyman, Mary E. Gerritsen, Ruoyu Gong, Charles R. Holst |
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| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Time Factors
Lactams Macrocyclic Science Phthalic Acids Mitosis Cell Cycle Proteins HSP90 Heat-Shock Proteins Synthesis Phase Protein Serine-Threonine Kinases Biology Cell Growth Cell Line 03 medical and health sciences Fluorescence-Activated Cell Sorting 0302 clinical medicine Proto-Oncogene Proteins Drug Discovery Molecular Cell Biology Basic Cancer Research Benzoquinones Humans Image Cytometry Cellular Stress Responses 030304 developmental biology Genetics 0303 health sciences Multidisciplinary Cell Cycle Flow Cytometry High-Throughput Screening Assays 3. Good health High throughput analysis Cell staining Oncology 030220 oncology & carcinogenesis Genome Biology Medicine Azabicyclo Compounds Cell Division Cytometry Research Article Biotechnology |
| Zdroj: | PLoS ONE, Vol 6, Iss 3, p e17692 (2011) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | BackgroundMany 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.Methodology/principal findingsTo 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.Conclusions/significanceOur 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. |
| Databáze: | OpenAIRE |
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