Mitochondrial Functions of G1P3 in Breast Cancer Cells
Master of Science (MS)
Biological and Environmental Sciences
Date of Award
Breast Cancer remains the second leading cause of cancer-related deaths among American women mainly because of resistance to anti-estrogen therapies. Recently we reportedthat G1P3, an immuno-endocrine induced anti-apoptotic protein, is a mediator of anti-estrogenresistance in breast cancer. However, anti-apoptotic mechanisms of G1P3 in mitochondriaremain unclear. Based upon its localization into mitochondria, we hypothesized that G1P3augments ROS levels in mitochondria to regulate mitochondrial biogenesis to suppressapoptosis. Since localization within the mitochondria regulates the activity of a protein, submitochondriallocalization of G1P3 was determined.In fractionation studies, G1P3 localized intoinner mitochondrial membrane (IMM), suggesting a role for G1P3 in inner mitochondrialpermeabilization by preventing the opening of mitochondrial permeability transition pore, thecritical steps of intrinsic apoptosis process. ROS levels in G1P3 overexpressing cells weresignificantly higher than that of vector control cells (3.3 fold, P < 0.0001). Additionally, Ca2+ionophore ionomycin markedly increased ROS levels and mitochondrial fission in MCF-7vectorcells. However, in G1P3 overexpressing cells ionomycin resulted in mitochondrial fusion.Moreover, cyclosporine A (CSA), an inhibitor of MPTP, reversed mitochondrial fission in vector and fusion in G1P3 overexpressing cells. Taken together, our results suggest that G1P3 inhibitsMPTP opening and leads to mitochondrial fusion to antagonize apoptosis. Further delineation ofmolecular mechanism by which G1P3 regulates mitochondrial biogenesis and MPTP openingwould allow us to design novel strategies to inhibits its activity in cancer cells.
Biochemistry, Biophysics, and Structural Biology | Life Sciences
Khalel, Ashjan F., "Mitochondrial Functions of G1P3 in Breast Cancer Cells" (2014). Electronic Theses & Dissertations. 585.