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Mechanisms of Interfering with HPV-Induced Carcinogenesis by Natural Products

Tschantz Chaney, Deidra Renee
http://rave.ohiolink.edu/etdc/view?acc_num=kent1259084071

Abstract Details

2009, PHD, Kent State University, College of Arts and Sciences / School of Biomedical Sciences.
Human papillomavirus (HPV)-induced uterine cervical cancer is one of the most prevalent cancers in women world-wide. HPV is a small DNA tumor virus that can infect the basal cells of the skin. Once infection occurs, the virus depends on the host cell machinery for maintenance of the viral life cycle. Progression to cervical cancer may occur when HPV DNA accidentally integrates into the host cell genome. Integration permits the continuous expression of two viral oncogenes, E6 and E7, which interfere with the function of two tumor suppressor proteins, p53 and retinoblastoma, respectively. E6 protein, through the complex with E6-AP, an ubiquitin ligase, causes degradation of p53 in the ubiquitin proteasome pathway. Thus, p53 is no longer available to respond to induce apoptosis. Recent studies in our laboratory have shown that a plant lignan from the creosote bush, 3’-O-methyl-nordihydroguaiaretic acid (3’-O-methyl-NDGA), can interfere with the expression of E6. Real-time RT-PCR analysis of full-length E6 mRNA shows that treatment of CaSki cells (HPV type 16) with lignan causes a six-fold reduction in E6 expression within 24 hours. 3’-O-methyl-NDGA is not toxic to normal keratinocytes, the host cell for HPV infection. Trypan blue studies show that normal cell viability remained close to 80% following treatment with lignans for 48 hours. Previous data show that HPV-positive cells undergo 60-70% apoptosis following treatment. 3’-O-methyl-NDGA has also been shown to be slightly toxic to precancerous cells. p53 is stabilized in these cells followed by induction of p21 and Bax. Initially, the lignan appears to be interfering with cell proliferation allowing a chance for damage repair. The inability for repair causes an induction of Bax protein followed shortly thereafter by apoptosis. Limiting toxicity to normal cells while producing an effective induction of apoptosis in both precancerous and cancer cells is an important aspect of developing novel approaches to interfere with HPV-induced carcinogenesis.
Angelo DeLucia, PhD (Advisor)
Jon Walro, PhD (Committee Member)
John Stalvey, PhD (Committee Member)
Richard Londraville, PhD (Committee Member)
Bansidhar Datta, PhD (Committee Member)
180 p.
Molecular Biology
human papillomavirus; natural lignans; E6 oncogene; p53

Recommended Citations

Citations

  • Tschantz Chaney, D. R. (2009). Mechanisms of Interfering with HPV-Induced Carcinogenesis by Natural Products [Doctoral dissertation, Kent State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=kent1259084071

    APA Style (7th edition)

  • Tschantz Chaney, Deidra. Mechanisms of Interfering with HPV-Induced Carcinogenesis by Natural Products. 2009. Kent State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=kent1259084071.

    MLA Style (8th edition)

  • Tschantz Chaney, Deidra. "Mechanisms of Interfering with HPV-Induced Carcinogenesis by Natural Products." Doctoral dissertation, Kent State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=kent1259084071

    Chicago Manual of Style (17th edition)

kent1259084071
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© 2009, all rights reserved.
This open access ETD is published by Kent State University and OhioLINK.