All ETDs from UAB

Advisory Committee Chair

Richard S Jope

Advisory Committee Members

Gail V W Johnson

Xiaohua Li

Scott Wilson

Tong Zhou

Document Type

Dissertation

Date of Award

2008

Degree Name by School

Doctor of Philosophy (PhD) School of Medicine

Abstract

Cancer is a common disease that causes high rates of lethality. Resistance to cancer therapy is one major obstacle for producing an effective cancer treatment. Clarifying mechanisms of cancer development, such as resistance to apoptosis and metastasis, can provide important information for developing effective cancer treatment strategies. In the present study, DDX3 was demonstrated to have effects on both responses to cancer treatment and cancer development. DDX3 together with glycogen synthase kinase-3 (GSK-3) was found to impede death receptor-induced apoptosis, which is important because death receptors are activated by some cancer treatments. Additionally, DDX3 was shown to regulate two proteins critical in cancer, p53 and Snail. Extrinsic apoptotic signaling induced by death receptors, especially TRAIL-R2, is a new method of anti-tumor therapy. However, 50% of cancer cells develop resistance to this therapy (LeBlanc and Ashkenazi 2003). Thus, finding mechanisms that regulate this extrinsic apoptosis pathway is important to overcome this resistance. In this study, we found that DDX3 associates with GSK3 and cellular inhibitor of apoptosis protein (cIAP- 1) to form a complex that binds to death receptors to inhibit activation of the apoptosis cascade. Blocking the actions of DDX3 or GSK3 potentiated apoptosis induced by stimulation of four different death receptors in several types of cells. Thus, DDX3 and GSK3 are regulatory proteins bound to the death receptor that counterbalance apoptotic iii signaling upon death receptor stimulation. Targeting DDX3 or GSK3 could be a useful therapy in combinations with stimulation of death receptors for resistant cancer treatment. DDX3 was also found to stabilize p53, an important tumor suppressor gene, and Snail, an essential protein for promoting metastasis. The association of DDX3 with p53 and with Snail may contribute to reducing their nuclear export and subsequent degradation, therefore causing their nuclear retention and accumulation. Overall, this study uncovers novel actions of DDX3 affecting both cancer progression and treatment. These results provide a new potential target to overcome resistance to cancer therapy and to develop more specific and powerful therapeutic strategies.

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