Advisory Committee Chair
Aimee Landar
Advisory Committee Members
Victor Darley-Usmar
Dale Dickinson
Jeannette Doeller
Andra Frost
Document Type
Dissertation
Date of Award
2009
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.
Recommended Citation
Diers, Anne R., "Regulation of redox signaling by lipid electrophiles in breast cancer" (2009). All ETDs from UAB. 1521.
https://digitalcommons.library.uab.edu/etd-collection/1521