All ETDs from UAB

Advisory Committee Chair

Aimee Landar

Advisory Committee Members

Victor Darley-Usmar

Dale Dickinson

Jeannette Doeller

Andra Frost

Document Type

Dissertation

Date of Award

2010

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

A number of steps in breast cancer progression and metastasis are regulated by redox signaling pathways. Electrophilic lipids such as 15-deoxy-delta12,14-Prostaglandin J2 (15d-PGJ2) are mediators of redox signaling pathways because of their ability to modify critical cysteine residues (thiols) in redox-sensitive proteins. In this thesis, we examine the effect of lipid electrophiles such as 15d-PGJ2 and others on redox signaling pathways in breast cancer. Furthermore, we develop new strategies to regulate cancer cell behavior in response to lipid electrophiles using three strategies: 1) through organelle-specific targeting of electrophiles 2) by exploiting the concentration-dependence of effects of electrophiles, and 3) utilizing electrophiles which modify alternate target proteins. We synthesized a novel mitochondrially-targeted analog of 15d-PGJ2 (mito-15d-PGJ2) and found that it was more potent at initiating intrinsic apoptotic cell death and was less effective at upregulating the expression of the intracellular antioxidants heme oxygenase-1 and glutathione than untargeted 15d-PGJ2. In addition, we demonstrated that 15d-PGJ2, at sub-lethal concentrations, attenuated migration, stimulated focal adhesion disassembly, and caused extensive reorganization of the F-actin cytoskeleton. Moreover, we defined a role for the redox-sensitive p38 MAP kinase signaling pathway in mediating these effects. These results suggest a potential anti-metastatic activity of 15d-PGJ2. Finally, by comparing the biological responses of 15d-PGJ2 to a structurally related lipid electrophile, Prostaglandin A1 (PGA1), we showed that the effects of 15d-PGJ2 on the F-actin cytoskeleton and cell migration were specific for 15d-PGJ2 and cannot be recapitulated using PGA1. Taken together, our work now provides a basis for the use of these strategies to fine-tune biological responses to electrophiles, as well as deeper understanding of the role of redox signaling by lipid electrophiles in the regulation of breast cancer and metastasis.

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