Mooney Steven M, Jolly Mohit Kumar, Levine Herbert, Kulkarni Prakash
Department of Biology, University of Waterloo, Waterloo, ON N2L 3G1, Canada.
Center for Theoretical Biological Physics, Rice University, Houston, TX 77005; Department of Bioengineering, Rice University, Houston, TX 77005, USA.
Asian J Androl. 2016 Sep-Oct;18(5):704-10. doi: 10.4103/1008-682X.183570.
A striking characteristic of cancer cells is their remarkable phenotypic plasticity, which is the ability to switch states or phenotypes in response to environmental fluctuations. Phenotypic changes such as a partial or complete epithelial to mesenchymal transition (EMT) that play important roles in their survival and proliferation, and development of resistance to therapeutic treatments, are widely believed to arise due to somatic mutations in the genome. However, there is a growing concern that such a deterministic view is not entirely consistent with multiple lines of evidence, which indicate that stochasticity may also play an important role in driving phenotypic plasticity. Here, we discuss how stochasticity in protein interaction networks (PINs) may play a key role in determining phenotypic plasticity in prostate cancer (PCa). Specifically, we point out that the key players driving transitions among different phenotypes (epithelial, mesenchymal, and hybrid epithelial/mesenchymal), including ZEB1, SNAI1, OVOL1, and OVOL2, are intrinsically disordered proteins (IDPs) and discuss how plasticity at the molecular level may contribute to stochasticity in phenotypic switching by rewiring PINs. We conclude by suggesting that targeting IDPs implicated in EMT in PCa may be a new strategy to gain additional insights and develop novel treatments for this disease, which is the most common form of cancer in adult men.
癌细胞的一个显著特征是其显著的表型可塑性，即能够根据环境波动改变状态或表型。诸如部分或完全上皮-间质转化（EMT）等表型变化在癌细胞的存活、增殖以及对治疗产生抗性的过程中发挥着重要作用，人们普遍认为这些变化是由基因组中的体细胞突变引起的。然而，越来越多的人担心这种确定性观点并不完全符合多项证据，这些证据表明随机性在驱动表型可塑性方面可能也起着重要作用。在此，我们讨论蛋白质相互作用网络（PINs）中的随机性如何在决定前列腺癌（PCa）的表型可塑性中发挥关键作用。具体而言，我们指出驱动不同表型（上皮、间质以及混合上皮/间质）转变的关键因子，包括ZEB1、SNAI1、OVOL1和OVOL2，都是内在无序蛋白（IDPs），并讨论分子水平的可塑性如何通过重新连接PINs导致表型转换中的随机性。我们最后提出，针对PCa中涉及EMT的IDPs可能是一种新策略，有助于进一步了解这种疾病并开发新的治疗方法，前列腺癌是成年男性中最常见的癌症形式。
