Date of Award

2012

Degree Type

Dissertation

Department

Chemistry

First Advisor

Kalafatis, Michael

Subject Headings

Protein kinase CK2, Acids, Cervix uteri -- Cancer, Ellagic acid, CK2, Cervical Cancer, HPV, IAP's

Abstract

Targeting CK2 for cancer therapy has proven effective in inhibiting tumor growth in several histology's. The main goal of this study was to acquire pre-clinical data on a naturally occurring CK2-inhibitor (ellagic acid) in support of a human clinical trial. In vitro analysis included testing the spectrum of ellagic acid anti-cancer activity, defining the mode of growth inhibition in cancer cells and its impact on biochemical and molecular pathways. In vivo studies included determination of ellagic acid inhibitory effect in animal tumor models and toxicity analysis. We found that CK2 inhibition mediated by ellagic acid, was effective in inhibiting the growth of a wide spectrum of human cancer cells. These include breast cancer (MCF-7), kidney cancer (ACHN), colon adenocarcinoma (SW480), glioblastoma (U87), prostate cancer (DU-145), melanoma (WM164) and HPV -positive (HeLa) and -negative (C33A) cervical carcinomas. We used HeLa and C33A cell lines to determine EA mechanisms of action and impact on oncogenic, proliferative, and apoptotic pathways. Since CK2 controls over 300 target proteins involved in major biochemical and molecular pathways, we found that ellagic acid treatment was able to inhibit HPV oncogene expression, interrupt oncogenic pathways and induce anti-proliferative and pro-apoptotic pathways in HeLa cells. In C33A cells, CK2 inhibition bypassed tumor suppressor p53 and pRb mutation and induced apoptosis by inhibition of anti-apoptotic proteins IAPs. Comparing HeLa and C33A cells response to ellagic acid treatment, C33A cells were more sensitive to ellagic acid treatment compared to HeLa. The expression of HPV oncogenes in HeLa cells could delay HeLa response to death stimuli exerted by CK2 inhibition. CK2 inhibition and subsequent IAPs repression is the common event occurring in HeLa and C33A cells

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