K Vitamins- A New Class of Liver Cell Growth Inhibitors

描述（由申请人提供）：K维生素在肝癌中代谢失调。我们在第一项研究中发现，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），导致ERK的深度和长时间磷酸化，这是其生长抑制作用所必需的。现在建议对其机制进行研究。我们的工作假设是，我们的模型类似物cpd5抑制Cdc25A（和其他PTPs），导致选定蛋白长时间和强烈的磷酸化，从而导致生长抑制。特别是，ERK被磷酸化并转运到细胞核。MEK抑制剂消除了所有的cpd5效应。具体目的是考察：1。cpd5与Cdc25A的相互作用及其对细胞的影响。2. ERK磷酸化和核易位延长的意义和机制。3. 延长ERK激活对cpd5和新的类似物抑制细胞生长的影响。4. 为了测试cpd5对HCC生长和化学大鼠肝癌发生的长期体内影响，并评估一些新的，更有效的类似物Cdc25抑制剂的细胞和体内作用，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)发现了一种全新药物（维生素K类似物）的更有效的PTP抑制剂；(b)延长ERK磷酸化是生长抑制的重要介质（以前与生长刺激有关）的观点；(c)数据支持的假设，即细胞周期调节PTPs的Cdc25组可能控制ERK磷酸化；(d)这些新的维生素K类似物在体内也起作用，可能通过与在体外发现的相似的机制，具有治疗和预防体内肝癌形成的潜力。

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.