Squamous cell carcinoma is the major cancer diagnosed in the head and neck and oral cavity. Head and neck squamous cell carcinoma (HNSCC) is a tremendous public health challenge; it is the third most prevalent cancer with only breast and colorectal cancers being more common. Despite technological advances in surgery, radiotherapy and chemotherapy for patients who suffer from head and neck cancer, the survival-rate has remained un-improved in the last two decades indicating our ability to treat patients has reached a plateau. Recent surges in the number of young people who develop HNSCC, and our limited ability to satisfactorily care for those who suffer from this disease have fueled an intense search for new treatment strategies. An increasing body of evidence has indicated that malignant transformation of oral keratinocytes can be modulated by a wide variety of genetic mutations and misregulated cell signaling networks. Many signaling intermediates from these pathways, such as NF-kappaB, are also known to modulate resistance to chemotherapy-induced tumor cell death. The work presented in this dissertation is focused toward the elucidation of novel gene therapy and chemotherapy strategies to manipulate the signaling machinery in malignant oral keratinocytes to potentiate or directly induce cell death. Upon completion of this work we have: (1) provided a molecular basis for gene therapy treatment of head and neck cancer with a super repressor of IkappaBalpha to inhibit NF-kappaB-mediated survival and chemoresistance; (2) demonstrated that the proteasome inhibitor PS-341 (Velcade) induces ER stress and reactive oxygen species to kill HNSCC cell in vitro; and (3) elucidated a mechanism by which ATF-4, induced following PS-341-mediated ER stress, transcriptionally regulates the pro-apoptotic protein Noxa prior to cell death in cisplatin-resistant head and neck cancer cells. Furthermore, we have demonstrated that proteasome inhibition induces cell death through two distinct apoptotic mechanisms. PS-341 simultaneously induced caspase 12-dependent stress-specific apoptosis, and also activated the intrinsic (mitochondrion-mediated) apoptosis pathway. Our work has established that NF-kappaB and ER stress can be modulated to potentiate chemotherapy-induced tumor cell death in head and neck squamous cell carcinoma.Ph.D.DentistryHealth and Environmental SciencesMedicineOncologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/125082/2/3186632.pd
