K Vitamins- A New Class of Liver Cell Growth Inhibitors

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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.