HSP90 Inhibition and Cellular Stress Elicits Phenotypic Plasticity in Hematopoietic Differentiation
| Autor: | Emine C. Koc, Jennifer M. Napper, Seth Deskins, Sarah-Leigh Govender, Abdalla A. Lawag, Manaf El-hamdani, Nickolas A. Bacon, Vincent E. Sollars, Caroline A. Hunter |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Lactams Macrocyclic Biology Epigenesis Genetic Histones 03 medical and health sciences Mice Downregulation and upregulation Stress Physiological cellular stress stem cells Cell Plasticity Benzoquinones Animals HSP90 Epigenetics HSP90 Heat-Shock Proteins Research Articles Phenotypic plasticity Stem Cell Factor cell plasticity epigenetics Mechanism (biology) molecular evolution Granulocyte-Macrophage Colony-Stimulating Factor Acetylation Cell Differentiation Cell Biology Hematopoietic Stem Cells Cell biology Hematopoiesis Haematopoiesis 030104 developmental biology Cancer cell Stem cell Developmental Biology Biotechnology Signal Transduction |
| Zdroj: | Cellular Reprogramming |
| ISSN: | 2152-4998 |
| Popis: | Cancer cells exist in a state of Darwinian selection using mechanisms that produce changes in gene expression through genetic and epigenetic alteration to facilitate their survival. Cellular plasticity, or the ability to alter cellular phenotype, can assist in survival of premalignant cells as they progress to full malignancy by providing another mechanism of adaptation. The connection between cellular stress and the progression of cancer has been established, although the details of the mechanisms have yet to be fully elucidated. The molecular chaperone HSP90 is often upregulated in cancers as they progress, presumably to allow cancer cells to deal with misfolded proteins and cellular stress associated with transformation. The objective of this work is to test the hypothesis that inhibition of HSP90 results in increased cell plasticity in mammalian systems that can confer a greater adaptability to selective pressures. The approach used is a murine in vitro model system of hematopoietic differentiation that utilizes a murine hematopoietic stem cell line, erythroid myeloid lymphoid (EML) clone 1, during their maturation from stem cells to granulocytic progenitors. During the differentiation protocol, 80%–90% of the cells die when placed in medium where the major growth factor is granulocyte–macrophage-colony stimulating factor. Using this selection point model, EML cells exhibit increases in cellular plasticity when they are better able to adapt to this medium and survive. Increases in cellular plasticity were found to occur upon exposure to geldanamycin to inhibit HSP90, when subjected to various forms of cellular stress, or inhibition of histone acetylation. Furthermore, we provide evidence that the cellular plasticity associated with inhibition of HSP90 in this model involves epigenetic mechanisms and is dependent upon high levels of stem cell factor signaling. This work provides evidence for a role of HSP90 and cellular stress in inducing phenotypic plasticity in mammalian systems that has new implications for cellular stress in progression and evolution of cancer. |
| Databáze: | OpenAIRE |
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