Lawag Abdalla A, Napper Jennifer M, Hunter Caroline A, Bacon Nickolas A, Deskins Seth, El-Hamdani Manaf, Govender Sarah-Leigh, Koc Emine C, Sollars Vincent E
1 Department of Biomedical Sciences, Joan C. Edwards School of Medicine at Marshall University , Huntington, West Virginia.
2 Department of Natural Sciences, Shawnee State University , Portsmouth, Ohio.
Cell Reprogram. 2017 Oct;19(5):311-323. doi: 10.1089/cell.2017.0001. Epub 2017 Sep 14.
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.
癌细胞通过遗传和表观遗传改变产生基因表达变化的机制，处于达尔文选择状态，以促进其生存。细胞可塑性，即改变细胞表型的能力，可通过提供另一种适应机制，协助癌前细胞发展为完全恶性肿瘤时的生存。细胞应激与癌症进展之间的联系已经确立，尽管其机制细节尚未完全阐明。分子伴侣热休克蛋白90（HSP90）在癌症进展过程中通常会上调，推测是为了让癌细胞应对与转化相关的错误折叠蛋白和细胞应激。这项工作的目的是检验以下假设：在哺乳动物系统中抑制HSP90会导致细胞可塑性增加，从而赋予对选择压力更大的适应性。所采用的方法是一种造血分化的小鼠体外模型系统，该系统在从干细胞成熟为粒细胞祖细胞的过程中，利用小鼠造血干细胞系红系髓系淋巴系（EML）克隆1。在分化过程中，当置于主要生长因子为粒细胞-巨噬细胞集落刺激因子的培养基中时，80%-90%的细胞会死亡。利用这个选择点模型，当EML细胞能够更好地适应这种培养基并存活时，它们的细胞可塑性会增加。发现当暴露于格尔德霉素以抑制HSP90、受到各种形式的细胞应激或抑制组蛋白乙酰化时，细胞可塑性会增加。此外，我们提供证据表明，在该模型中与抑制HSP90相关的细胞可塑性涉及表观遗传机制，并且依赖于高水平的干细胞因子信号传导。这项工作为HSP90和细胞应激在诱导哺乳动物系统中表型可塑性方面的作用提供了证据，这对癌症进展和演变中的细胞应激具有新的意义。
