K Vitamins- A New Class of Liver Cell Growth Inhibitors

描述(申请人提供)：K维生素代谢在肝癌中是失调的。在我们的第一项资助中，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)，导致深刻和长期的ERK磷酸化，这是其抑制生长作用所必需的。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CPD 5抑制CDc25A(和其他PTP)，导致选定蛋白质长期而强烈的磷酸化，从而导致生长抑制。特别是，ERK被磷酸化并转移到细胞核。MEK抑制剂可消除CPD-5的所有作用。具体目的是检查：1.CPD 5与CDc25A的相互作用及其细胞后果。2.延长ERK磷酸化和核转位的意义及机制。3.CPD-5及其类似物对ERK激活时间延长对细胞生长抑制的影响。4.鉴于CDC25高表达是多种肿瘤类型的特征，本研究旨在检测CPD-5对肝癌生长的长期体内效应和对化学致癌的大鼠肝癌的抑制作用，并评价一些新的、更有效的类似物CDC25的细胞和体内作用。5.这项工作的新颖性在于：(A)发现了一种全新的药物(K维生素类似物)的更有效的PTP抑制剂；(B)认为延长ERK磷酸化是抑制生长的重要介质(它以前与生长刺激有关)；(C)有数据支持的假设，即CDC25组细胞周期调节PTP可能控制ERK磷酸化；(D)这些新型K维生素类似物在体内也起作用，可能通过与体外发现的类似机制，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.