PRUNE_1 INVOLMENT IN TNBC ENHANCING CANCER METABOLISM

Tumor initiation and progression depend on the metabolic reprogramming of cancer cells to meet heightened energy and biosynthetic demands. Triple-Negative Breast Cancer (TNBC), characterized by the absence of hormone and HER2 receptors, exhibits high glycolytic and oxidative phosphorylation (OXPHOS) activity, contributing to poor prognosis and metastasis. The ATP5A1 protein, a key component of mitochondrial ATP synthase, plays a central role in energy metabolism and is linked to cancer-specific metabolic alterations, including the Warburg effect. Polyphosphates (PolyP) emerge as critical modulators of ATP synthesis through their degradation by Prune1, which facilitates ADP-ATP conversion and supports mitochondrial function under stress. Prune1 overexpression is associated with metastasis, epithelial-mesenchymal transition (EMT), and poor prognosis in cancers. It modulates intracellular pathways, including WNT and TGF-β signaling, through interactions with cytoskeleton proteins and kinases. Using a genetically engineered mouse model (GEMM) of metastatic TNBC (MMTV-Prune1/Wnt1), Prune1 was found to enhance glycolysis and OXPHOS, promoting lung metastases by inhibiting GSK-3 activity. Prune1's mitochondrial localization and interaction with ATP5A1 highlight its role in OXPHOS-mediated ATP production. The Prune1 inhibitor (LEO-AA7.5(S)T) was shown to impair tumor metastasis, enhance cell adhesion, and inhibit metabolic reprogramming by activating GSK-3 and NDPK-A. These findings underscore Prune1 as a potential therapeutic target for high-risk metastatic TNBC and cancers with altered glycolysis and OXPHOS pathways.