DOI
https://doi.org/10.25772/NS18-VJ57
Defense Date
2016
Document Type
Thesis
Degree Name
Master of Science
Department
Physiology and Biophysics
First Advisor
Dr. Hisashi Harada
Second Advisor
Dr. Andrei I. Ivanov
Third Advisor
Dr. Qinglian Liu
Abstract
The primary focus of this research is the mechanisms of cell death in head and neck squamous cell carcinoma (HNSCC) treatment. These cancers typically originate in squamous cells that line the moist mucosal surfaces of head and neck. HNSCC is commonly treated with a platinum based agent, cisplatin. While the drug does offer strong antitumor effects, its prolonged use often results in tumor-acquired resistance, which limits treatment effectiveness. We have shown that cisplatin treatment induces the expression of a pro-apoptotic BCL-2 family member Noxa, which then initiates caspase- dependent apoptosis through its binding and sequestration of pro-survival protein MCL-1 for its inactivation. Without Noxa induction, cell death is significantly reduced when treating HNSCCs with cisplatin. The objectives of this study are (1) to determine the molecular mechanisms by which Noxa induces cell death in HNSCC cells; (2) to determine the molecular mechanisms of cisplatin-resistance in isogenic HNSCC cell lines.
We observed an increase of apoptosis by ectopic expression of Noxa in all HNSCC cell lines tested, but not in immortalized human normal oral keratinocytes (NOK), suggesting that Noxa overexpression is sufficient to induce tumor-specific cell death. Noxa-induced cell death was mediated by BAX and BAK activation. BAK activation was mediated through Noxa binding to MCL-1, but not BCL-XL. Cisplatin- resistant cells induced less Noxa and apoptosis, supporting that Noxa induction is prerequisite for apoptosis induced by cisplatin. Taken together, Noxa induces tumor- specific cell death in HNSCC cells primarily through BAX and BAK activation, which suggests the therapeutic potential of this protein.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
5-12-2016