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Therapeutic Reactivation of the p53 Tumor Suppressor Protein in HPV-Positive Cervical Cancer Cells by the Creosote Bush Lignan 3’-O-Methyl-Nordihydroguaiaretic Acid

Allen, Kristi Lynne

Abstract Details

2007, PHD, Kent State University, College of Biomedical Sciences.
Persistent Human Papillomavirus (HPV) infection is the primary risk factor for the development of cervical carcinoma, a major disease burden in women worldwide. Over 90 percent of cancers of the uterine cervix and at least 50 percent of other anogenital tumors contain high-risk HPV DNA. High-risk HPV’s exert their oncogenic effects on infected cells when viral DNA becomes integrated by uncontrollably expressing the viral gene products E6 and E7. E6 and E7 proteins interfere with the functions of the cellular tumor suppressors p53 protein and retinoblastoma protein (pRB105). High risk HPV E6 forms a complex with p53 and the E6-AP ubiquitin ligase and facilitates the degradation of p53 through the ubiquitin proteasome pathway. Similarly, HPV E7 binds to pRB105 and inhibits its ability to interact with factors associated with the cell cycle. Recent studies in our laboratory have identified a lignan from the creosote bush, 3’-O-methyl-nordihydroguaiaretic acid (3’-O-methyl-NDGA), that can subvert viral oncogene functions and reactivate the p53 tumor suppressor pathway within treated tumor cells. Western blot analysis has shown that p53 is stabilized in HPV-positive cervical cancer cells treated with the lignan. The stabilized p53 is transcriptionally active as shown by p53-luciferase reporter assay and the induction of the pro-apoptotic PUMA and bax proteins. Apoptosis, as measured and confirmed by caspase induction, TUNEL assay, and annexin V binding was observed in HPV-positive tumor cells following treatment with the lignan. Apoptosis was not observed in HPV-negative tumor cells or tumor cells lacking wild type p53. This compound may represent a novel small molecule therapy against HPV-induced tumors and precancerous lesions of the uterine cervix.
Angelo DeLucia (Advisor)
160 p.

Recommended Citations

Citations

  • Allen, K. L. (2007). Therapeutic Reactivation of the p53 Tumor Suppressor Protein in HPV-Positive Cervical Cancer Cells by the Creosote Bush Lignan 3’-O-Methyl-Nordihydroguaiaretic Acid [Doctoral dissertation, Kent State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=kent1176432164

    APA Style (7th edition)

  • Allen, Kristi. Therapeutic Reactivation of the p53 Tumor Suppressor Protein in HPV-Positive Cervical Cancer Cells by the Creosote Bush Lignan 3’-O-Methyl-Nordihydroguaiaretic Acid. 2007. Kent State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=kent1176432164.

    MLA Style (8th edition)

  • Allen, Kristi. "Therapeutic Reactivation of the p53 Tumor Suppressor Protein in HPV-Positive Cervical Cancer Cells by the Creosote Bush Lignan 3’-O-Methyl-Nordihydroguaiaretic Acid." Doctoral dissertation, Kent State University, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=kent1176432164

    Chicago Manual of Style (17th edition)