Department of Molecular Biosciences, Northwestern University, Evanston, Illinois, United States of America.
PLoS One. 2012;7(2):e32318. doi: 10.1371/journal.pone.0032318. Epub 2012 Feb 29.
Snail family proteins are core EMT (epithelial-mesenchymal transition) regulatory factors that play essential roles in both development and disease processes and have been associated with metastasis in carcinomas. Snail factors are required for the formation of neural crest stem cells in most vertebrate embryos, as well as for the migratory invasive behavior of these cells. Snail factors have recently been linked to the formation of cancer stem cells, and expression of Snail proteins may be associated with tumor recurrence and resistance to chemotherapy and radiotherapy. We report that Co(III)-Ebox is a potent inhibitor of Snail-mediated transcriptional repression in breast cancer cells and in the neural crest of Xenopus. We further show that the activity of Co(III)-Ebox can be modulated by temperature, increasing the utility of this conjugate as a Snail inhibitor in model organisms. We exploit this feature to further delineate the requirements for Snail function during neural crest development, showing that in addition to the roles that Snail factors play in neural crest precursor formation and neural crest EMT/migration, inhibition of Snail function after the onset of neural crest migration leads to a loss of neural crest derived melanocytes. Co(III)-Ebox-mediated inhibition therefore provides a powerful tool for analysing the function of these core EMT factors with unparalleled temporal resolution. Moreover, the potency of Co(III)-Ebox as a Snail inhibitor in breast cancer cells suggests its potential as a therapeutic inhibitor of tumor progression and metastasis.
蜗牛家族蛋白是 EMT（上皮-间质转化）的核心调节因子，在发育和疾病过程中发挥着重要作用，并与癌转移有关。蜗牛因子是大多数脊椎动物胚胎中神经嵴干细胞形成以及这些细胞迁移侵袭行为所必需的。最近，蜗牛因子与癌症干细胞的形成有关，Snail 蛋白的表达可能与肿瘤复发以及对化疗和放疗的耐药性有关。我们报告 Co(III)-Ebox 是一种有效的乳腺癌细胞和非洲爪蟾神经嵴中 Snail 介导的转录抑制物抑制剂。我们进一步表明，Co(III)-Ebox 的活性可以通过温度调节，增加了该共轭物作为模型生物中 Snail 抑制剂的实用性。我们利用这一特点进一步阐明了 Snail 功能在神经嵴发育过程中的要求，表明除了 Snail 因子在神经嵴前体形成和神经嵴 EMT/迁移中所起的作用外，抑制神经嵴迁移开始后的 Snail 功能会导致神经嵴衍生的黑色素细胞丢失。因此，Co(III)-Ebox 介导的抑制为分析这些核心 EMT 因子的功能提供了一个强大的工具，具有无与伦比的时间分辨率。此外，Co(III)-Ebox 作为乳腺癌细胞中 Snail 抑制剂的效力表明其作为肿瘤进展和转移的治疗抑制剂具有潜力。
