Depletion of dAKAP1 signaling complexes accompanies pathological changes in mitochondrial dynamics during breast cancer progression
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The dual-specificity A-kinase anchoring protein 1 (dAKAP1) is a mitochondrial anchoring protein responsible for recruiting protein kinase A (PKA), along with other signaling molecules, to the outer mitochondrial membrane to influence mitochondrial dynamics. Through careful analysis of publicly available proteomic and transcriptomic datasets, we have observed a marked inverse correlation of known mesenchymal markers with dAKAP1 expression in breast cancer cell lines and tissues. Furthermore, dAKAP1 expression also correlated with both oxidative metabolism and decreased motility in breast cancer cell lines. These data suggest that dAKAP1 may be down-regulated at some stage in the process of epithelial-to-mesenchymal transition (EMT) and this regulation may influence the energetic and migratory phenotypes of tumor cells. Taken together, these correlative analyses provide an attractive foundation for the hypothesis that dAKAP1 influences critical signaling pathways involved in cell migration and thus, through its effects on mitochondrial morphology and function, differential expression of this protein can impact metastatic tumor progression. Using our correlative studies as a guide, we classified breast cancer cell lines into two subsets: (1) the glycolytic, invasive “dAKAP1-low” and (2) the oxidative, non-invasive “dAKAP1-high” cell lines. We then used molecular biology and live-cell imaging approaches to determine how the cells’ physiology changes when dAKAP1 expression is altered. We found that dAKAP1 depletion reduced mitochondrial membrane potential and influenced mitochondrial dynamics through the regulation of mitochondrial fission in breast cancer cells. Furthermore, cells depleted of dAKAP1 and subjected to nutrient deprivation were more susceptible to decreases in viability. Conversely, increased dAKAP1 expression significantly reduced the motility of migratory cells in a PKA anchoring-dependent manner. We propose a model in which expression of dAKAP1 is temporally regulated as cancer cells progress from primary tumor to metastatic mesenchymal-like cells. Understanding how dAKAP1 expression influences mitochondrial dynamics and the migratory mechanisms of tumor cells could help serve as a foundation for future rational drug design for the prevention of dangerous metastases.
- Pharmacology