Abstract

High-risk human papillomaviruses (HR-HPVs) cause nearly all cases of cervical cancer. HPV 16 E6, one of two viral oncogenes, protects cells from apoptosis by binding to and accelerating the degradation of several apoptotic proteins, including caspase 8 and p53. We proposed that blocking the interactions between HPV E6 and its partners using small molecules had the potential to re-sensitize HPV+ cells to apoptosis. To test this prediction, we screened libraries of small molecules for candidates that could block E6/caspase 8 binding, and identified several candidates from different chemical classes. Testing hits for dose-dependency and specificity in vitro and for toxicity in a cell-based assay allowed us to select the two best candidates, myricetin and 6,7-dihydro-1H-imidazo[4,5-c] pyridine-6-carboxylic acid (DIPC), for further testing. Both compounds significantly and specifically inhibited the ability of E6 to bind in vitro to both caspase 8 and to E6AP, the protein that mediates p53 degradation. In addition, both compounds were able to increase caspase 3/7 activity and to sensitize HPV+ SiHa cells, but not HPV- C33A cells, to apoptosis induced by TRAIL, a cancer-specific ligand, as well as the chemotherapeutic agents doxorubicin and cisplatin. New therapies based on this work may improve treatment for HPV+ cancer patients.

LLU Discipline

Microbiology and Molecular Genetics

Department

Microbiology

School

Graduate Studies

First Advisor

Penelope J. Duerksen-Hughes

Second Advisor

Maria Filippova

Third Advisor

Daila S. Gridley

Fourth Advisor

John L. Krstenansky

Fifth Advisor

Ubaldo Soto

Sixth Advisor

Ron E. Swensen

Degree Name

Doctor of Philosophy (Medical Science)

Degree Level

Ph.D.

Year Degree Awarded

2013

Date (Title Page)

6-2013

Language

English

Library of Congress/MESH Subject Headings

Human papilloma virus; HPV E6

Type

Dissertation

Page Count

ix; 88 p.

Digital Format

PDF

Digital Publisher

Loma Linda University Libraries

Usage Rights

This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.

Collection

Loma Linda University Electronic Theses and Dissertations

Collection Website

http://scholarsrepository.llu.edu/etd/

Repository

Loma Linda University. Del E. Webb Memorial Library. University Archives

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