Mann 2019 Oncogene
|Mann J, Githaka JM, Buckland TW, Yang N, Montpetit R, Patel N, Li L, Baksh S, Godbout R, Lemieux H, Goping IS (2019) Non-canonical BAD activity regulates breast cancer cell and tumor growth via 14-3-3 binding and mitochondrial metabolism. Oncogene [Epub ahead of print].|
Abstract: The Bcl-2-associated death promoter BAD is a prognostic indicator for good clinical outcome of breast cancer patients; however, whether BAD affects breast cancer biology is unknown. Here we showed that BAD increased cell growth in breast cancer cells through two distinct mechanisms. Phosphorylation of BAD at S118 increased S99 phosphorylation, 14-3-3 binding and AKT activation to promote growth and survival. Through a second, more prominent pathway, BAD stimulated mitochondrial oxygen consumption in a novel manner that was downstream of substrate entry into the mitochondria. BAD stimulated complex I activity that facilitated enhanced cell growth and sensitized cells to apoptosis in response to complex I blockade. We propose that this dependence on oxidative metabolism generated large but nonaggressive cancers. This model identifies a non-canonical role for BAD and reconciles BAD-mediated tumor growth with favorable outcomes in BAD-high breast cancer patients.
Labels: MiParea: Respiration, nDNA;cell genetics Pathology: Cancer Stress:Cell death Organism: Human Tissue;cell: Endothelial;epithelial;mesothelial cell Preparation: Intact cells, Permeabilized cells Enzyme: Complex I
Coupling state: LEAK, ROUTINE, OXPHOS, ET Pathway: N, S, CIV, NS, ROX HRR: Oxygraph-2k