Date of Award

1-1-2016

Embargo Period

1-1-2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biochemistry and Molecular Biology

College

College of Graduate Studies

First Advisor

Besim Ogretmen

Second Advisor

L. Ashley Cowart

Third Advisor

Steven A. Rosenzweig

Fourth Advisor

Natalie Sutkowski

Fifth Advisor

Dennis Watson

Abstract

The five-year survival rate for head and neck squamous cell carcinoma (HNSCC) is 50% and has not improved since the 1960’s. Interestingly, patients with HNSCC associated with Human papillomavirus (HPV) infection demonstrate a 72% decrease in disease-specific mortality compared to HPV-negative HNSCC patients. As ceramide-mediated lethal mitophagy is known to play an important role in the response of HNSCC to treatment, we asked whether this novel form of cell death may be involved in the enhanced response. Using cell lines generated from HPV-negative or HPV-positive HNSCC tumors, we examined a possible role for ceramide signaling in response to cisplatin. We found that cisplatin did indeed induce ceramide-mediated lethal mitophagy in HNSCC cells and a tumor xenograft model, more strongly in HPV-positive than HPV-negative cells. Lethal mitophagy was enhanced by E7 expression, inhibited by Rb expression, and enhanced by E2F5 expression. Interestingly, we identified a non-canonical role for E2F5, in which its association with the mitochondrial fission protein Drp1 enhances ceramide-mediated mitophagy. Moreover, a peptide representing the putative Drp1-binding region of E2F5 elicited the same effects, and was effective in halting tumor growth in vivo when given in combination with cisplatin. These data are the first to identify a role for sphingolipid signaling in the enhanced response of HPV-associated HNSCC and define a detailed mechanism for the known enhanced response. Additionally, we identified a role for E2F5 in enhancing mitophagy by associating with Drp1, and generated a peptide that effectively sensitizes HPV-negative HNSCC to cisplatin by the same mechanism as observed in HPV-positive HNSCC.

Rights

All rights reserved. Copyright is held by the author.

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