Date of Graduation
Doctor of Philosophy (PhD)
Dr. Jeffrey Myers, MD, PhD
Dr. Timothy McDonnell, MD, PhD
Dr. Sunil Krishnan, MD
Dr. Peng Huang, MD, PhD
Dr. Zahid Siddik, PhD
Treatment of Head and Neck Squamous Cell Carcinoma, HNSCC, often requires multimodal therapy, including radiation therapy. The efficacy of radiotherapy in controlling locoregional recurrence, the most frequent cause of death from HNSCC, is critically important for patient survival. One potential biomarker to determine radioresistance is TP53, whose alterations are predictive of poor radiation response. The following work shows that the p53 transcriptional target, p21, is crucial in initiating and maintaining senescence in HNSCC, through its ability to regulate reactive oxygen species (ROS). With the use of a novel system to evaluate the impact of the TP53 missense mutations, we were able to distinguish that cells with a partially functional TP53, that are resistant to radiation induced senescence, were able to senescence under persistent exposure to low levels of the ROS, hydrogen peroxide, or with a transient overexpression of p21 in combination with radiation. Each of these treatments created long term elevation of ROS, which was not seen in radiation only treatment. This data demonstrates that the level of ROS is crucial in overcoming inhibition of radiation induced senescence when initiating a partially functional p53’s transcription of p21. In turn, p21’s ability to sustain elevated levels of ROS is necessary to allow for a long-term oxidative stress, ensuring an active p53-p21-ROS signaling loop with an end result of senescence.
We continued our work by investigating the mechanism by which mutp53 HNSCC cells were exhibiting their radioresistance. Noticing that mutp53 cells had a significantly higher baseline level of ROS, when compared to wtp53 cells, we were able to determine that these cells were able to sustain and thrive in a high ROS environment due to their ability to regulate proteins affiliated with elevated antioxidant levels. Observing that long term elevated p21 in combination with radiation or persistent exposure to elevated ROS alone were able to induce a significant level of senescence in partially functional TP53 HNSCC cells, we applied therapeutic approaches to mimic each condition, achieving promising results. This work emphasizes the importance of considering TP53 status when selecting a patient’s treatment options. Overall, our data offer a rationale to consider the use of either ROS inducing agents or therapies that increase p21 expression in combination with radiation.
as approaches in HNSCC cancer therapy.
head and neck cancer, reactive oxygen species, p53, p21, senescence