Document Type

Dissertation

Date of Degree

2013

Degree Name

PhD (Doctor of Philosophy)

Degree In

Free Radical and Radiation Biology

First Advisor

Prabhat C. Goswami

Abstract

Radiation is a common mode of cancer therapy that is well known to generate reactive oxygen species leading to cell damage and death. However, there are many limitations to radiation therapy including normal tissue toxicity and the presence of quiescent cancer cells that are radio-resistant. There are many factors that regulate normal and cancer cell radiation response including the cellular redox environment which includes a complex network of antioxidants. In this study, two specific objectives will be explored: (A) SEPP1 regulation of normal cell toxicity; and (B) FoxM1 regulation of quiescence-associated radiation resistance in human oral squamous carcinoma cells. Results from DHE-oxidation analysis show that in irradiated proliferating normal cells there is a late ROS accumulation that occurs independent of cell cycle checkpoint activation and precedes cell death. Additionally, Q-RT-PCR and immunoblot analysis show an increase in Selenoprotein P (SEPP1) expression following radiation. SEPP1 is an extracellular glycoprotein with proposed selenium transport and antioxidant functions. However, pretreatment of normal cells with sodium selenite or overexpression of sepp1 is able to mitigate radiation-induced normal cell toxicity.

It is well-accepted that quiescent populations exist in most solid tumors and are often the reason for tumor recurrence. In this study, we see that quiescent head and neck cancer cells that are resistant to radiation have low basal expression of Forkhead box M1 (FoxM1) compared to proliferating cancer cells. FoxM1 is a transcription factor that has recently been implicated in the cellular response to oxidative stress. Results indicate that although basal expression is low in quiescent cells, following irradiation FoxM1 is increased in quiescent cancer cells but not in proliferating cancer cells. Additionally, pharmacological and genetic knockdown of FoxM1 led to sensitization of quiescent cancer cells indicating that FoxM1 inhibitors could be useful radiation sensitizers. Together, these objectives will help to identify possible treatment options to use in addition to radiation therapy to better target quiescence-associated resistant tumors and induce less normal cell toxicity.

Keywords

Cancer, FoxM1, Quiescence, Radiation, ROS, Selenoprotein P

Pages

xv, 159 pages

Bibliography

Includes bibliographical references (pages 141-159).

Copyright

Copyright 2013 Jaimee Claire Eckers

Share

COinS