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INHIBITON OF HUMAN PAPILLOMA VIRUS E6 ONCOGENE FUNCTION BY MAMMALIAN LIGNANS ACTIVATES THE P53 TUMOR SUPPRESSOR PROTEIN AND INDUCES APOPTOSIS IN CERVICAL CANCER CELLS

Awad, Keytam Salem
http://rave.ohiolink.edu/etdc/view?acc_num=kent1183405761

Abstract Details

2007, PHD, Kent State University, College of Biomedical Sciences.
Invasive uterine cervical cancer represents a major disease burden in women worldwide. Persistent Human Papillomavirus (HPV) infection is the primary risk factor for the development of cervical carcinoma. My research project involves exploring the mechanisms by which natural lignans may suppress viral oncogene function, as a novel approach to inhibit HPV induced precancerous and cancerous lesions. HPV is a small double-stranded DNA virus that contains two viral oncogenes, E6 and E7, that block the actions of the tumor suppressor proteins p53 and Rb, respectively. Our laboratory discovered that the mammalian lignans enterolactone and enterodiol increase the stability of the p53 protein and restore its functions, leading to the expression of downstream targets of p53. These mammalian lignans are derived from the parent plant lignans, secoisolariciresinol and matairesinol, via intestinal modifications of the compounds. My work has demonstrated that treatment with enterolactone represses E6 mRNA levels and E6 and E7 protein levels, with unchanging mRNA levels of p53 in HPV positive HeLa and CaSki cells. These results suggest that the ability of this lignan to induce stability of p53 occurs at a post-translational level. In addition, the functionality of p53 was examined. Induction of downstream targets of p53, such as p21 and Bax protein indicates that the p53 pathway is intact. Detection of apoptosis in cervical cancer cells was measured with a clonogenic survival assay, by activation of caspase 3, by DNA fragmentation using the TUNEL assay, as well as by repression of the anti-apoptotic protein Bcl-2. To test for the genotoxic potential of enterolactone, the comet assay was performed. The results failed to show formation of comet tails, indicating that no DNA damage was induced by the lignan. Taken together, these data unfold the mechanism by which enterolactone overcomes HPV mediated cell cycle dysregulation. More importantly, my data strongly suggests that a natural product may be useful in treating cervical cancer.
Angelo DeLucia (Advisor)
156 p.
Human papilloma virus; mammalian lignans; p53; E6 oncogene

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Citations

  • Awad, K. S. (2007). INHIBITON OF HUMAN PAPILLOMA VIRUS E6 ONCOGENE FUNCTION BY MAMMALIAN LIGNANS ACTIVATES THE P53 TUMOR SUPPRESSOR PROTEIN AND INDUCES APOPTOSIS IN CERVICAL CANCER CELLS [Doctoral dissertation, Kent State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=kent1183405761

    APA Style (7th edition)

  • Awad, Keytam. INHIBITON OF HUMAN PAPILLOMA VIRUS E6 ONCOGENE FUNCTION BY MAMMALIAN LIGNANS ACTIVATES THE P53 TUMOR SUPPRESSOR PROTEIN AND INDUCES APOPTOSIS IN CERVICAL CANCER CELLS. 2007. Kent State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=kent1183405761.

    MLA Style (8th edition)

  • Awad, Keytam. "INHIBITON OF HUMAN PAPILLOMA VIRUS E6 ONCOGENE FUNCTION BY MAMMALIAN LIGNANS ACTIVATES THE P53 TUMOR SUPPRESSOR PROTEIN AND INDUCES APOPTOSIS IN CERVICAL CANCER CELLS." Doctoral dissertation, Kent State University, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=kent1183405761

    Chicago Manual of Style (17th edition)

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© 2007, all rights reserved.
This open access ETD is published by Kent State University and OhioLINK.