K Vitamins- A New Class of Liver Cell Growth Inhibitors

描述（由申请方提供）：肝细胞瘤中维生素K代谢失调。在我们的第一个资助中，我们发现K维生素类似物是肝癌细胞生长的抑制剂，并选择性地抑制蛋白酪氨酸磷酸酶（PTPs），引起深刻和长期的ERK磷酸化，这是其生长抑制作用所必需的。现在建议审查这方面的机制。我们的工作假设是，我们的模型类似物，化合物5，抑制Cdc25A（和其他PTP），导致选定的蛋白质的长期和强烈的磷酸化，这导致生长抑制。特别地，ERK被磷酸化并易位到细胞核。MEK抑制剂消除所有化合物5的作用。 具体目的是研究：1。化合物5与Cdc25A的相互作用及其细胞后果。2. ERK磷酸化延长和核转位的意义及机制。3.通过化合物5和新类似物延长ERK激活对细胞生长抑制的后果。4.测试化合物5对HCC生长和化学大鼠肝癌发生的抑制的长期体内作用，并评估一些新的、更有效的Cdc25抑制剂类似物的细胞和体内作用，因为Cdc25过表达是许多肿瘤类型的特征。5.这项工作的新颖之处在于：（a）发现了一种全新的药物，（K维生素类似物）;（B）延长的ERK磷酸化是生长抑制的重要介质的观点（c）由数据支持的假说，即Cdc25组细胞周期调节PTP可以控制ERK磷酸化;（d）这些新的K维生素类似物也在体内起作用，并且可能通过与体外发现的类似机制起作用，并且具有治疗和预防体内肝细胞瘤形成的潜力。

DESCRIPTION (provided by applicant): K vitamin metabolism is dysregulated in hepatomas. We found in our first grant, that K vitamin analogs are inhibitors of hepatoma cell growth and selectively inhibit protein tyrosine phosphatases (PTPs), causing profound and prolonged ERK phosphorylation, which is essential to their growth inhibitory actions. It is now proposed to examine the mechanisms for this. Our working hypothesis is that our model analog, Cpd 5, inhibits Cdc25A (and other PTPs), causing prolonged and intense phosphorylation of selected proteins, which causes growth inhibition. In particular, ERK is phosphorylated and translocated to the nucleus. MEK inhibitors abrogate all the Cpd 5 effects. The specific aims are to examine: 1. The interactions of Cpd 5 with Cdc25A and the cellular consequences of these. 2. The significance and mechanisms of prolonged ERK phosphorylation and nuclear translocation. 3. The consequences of prolonged ERK activation for cell growth inhibition by Cpd 5 and new analogs. 4. To test the long-term in vivo effects of Cpd 5 on HCC growth and inhibition of chemical rat hepatocarcinogenesis and to evaluate the cellular and in vivo actions of some new, more potent analogs that are Cdc25 inhibitors, since Cdc25 over-expression is a feature of many tumor types. 5. The novelty of this work is (a) the finding of even more potent PTP inhibitors of an entirely new class of drug (K vitamin analogs); (b) the idea that prolonged ERK phosphorylation is an important mediator of growth inhibition (it was previously associated with growth stimulation); (c) the hypothesis, supported by data, that Cdc25 group of cell cycle regulating PTPs may control ERK phosphorylation; (d) these novel K vitamin analogs also work in vivo and likely by similar mechanisms as found in vitro and have the potential for both treating and preventing hepatoma formation in vivo.