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. ? ?
| Carr, Brian I; Akkiz, Hikmet; Üsküdar, Oguz et al. (2018) HCC with low- and normal-serum alpha-fetoprotein levels. Clin Pract (Lond) 15:453-464 |
| Carr, Brian I; Akkiz, Hikmet; Guerra, Vito et al. (2018) C-reactive protein and hepatocellular carcinoma: analysis of its relationships to tumor factors. Clin Pract (Lond) 15:625-634 |
| Akkiz, Hikmet; Carr, Brian I; Yalç?n K, Kendal et al. (2018) Characteristics of Hepatocellular Carcinoma Aggressiveness Factors in Turkish Patients. Oncology 94:116-124 |
| Akkiz, Hikmet; Carr, Brian I; Kuran, Sedef et al. (2018) Macroscopic Portal Vein Thrombosis in HCC Patients. Can J Gastroenterol Hepatol 2018:3120185 |
| Carr, Brian I; Guerra, Vito; Giannini, Edoardo G et al. (2016) A Liver Index and its Relationship to Indices of HCC Aggressiveness. J Integr Oncol 5: |
| Pan?oška, Petr; Skála, Lubomír; Nešet?il, Jaroslav et al. (2015) Evaluation of total hepatocellular cancer lifespan, including both clinically evident and preclinical development, using combined network phenotyping strategy and fisher information analysis. Semin Oncol 42:339-46 |
| D'Alessandro, Rosalba; Refolo, Maria Grazia; Lippolis, Catia et al. (2015) Modulation of Regorafenib effects on HCC cell lines by epidermal growth factor. Cancer Chemother Pharmacol 75:1237-1245 |
| Carr, Brian I; Lin, Chih-Yun; Lu, Sheng-Nan (2014) Platelet-related phenotypic patterns in hepatocellular carcinoma patients. Semin Oncol 41:415-21 |
| Refolo, Maria Grazia; D'Alessandro, Rosalba; Lippolis, Catia et al. (2014) Modulation of Doxorubicin mediated growth inhibition of hepatocellular carcinoma cells by platelet lysates. Anticancer Agents Med Chem 14:1154-60 |
| Pancoska, Petr; Carr, Brian I (2014) Macro- and micro-environmental factors in clinical hepatocellular cancer. Semin Oncol 41:185-94 |
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