Protein 4.1 R Suppresses Melanoma Progression by Inhibiting Glycolysis via the PI3K/AKT/mTOR Pathway

ABSTRACT Melanoma is a highly aggressive malignancy with strong metastatic potential. Protein 4.1 R, encoded by EPB41 , is a membrane cytoskeleton protein that plays an essential role in maintaining plasma membrane stability and cytoskeletal organization. Recent studies have indicated that the protein 4.1 R played a tumor‐suppressive role in multiple cancer types. However, the relationship between protein 4.1 R and glycolysis in melanoma remains unclear. In this study, we aimed to explore the relationship between protein 4.1 R expression and glucose metabolism and its mechanism of action in melanoma. Our results indicated that protein 4.1 R silencing significantly promoted the proliferation, migration and invasion of melanoma cells in vitro and accelerated tumor growth in vivo and increased glucose consumption, extracellular acidification rate, and lactate and ATP production, accompanied by reduced oxidative phosphorylation (OXPHOS). Protein 4.1 R silencing was associated with increased phosphorylation of PI3K, AKT and mTOR signaling components. Treatment with the PI3K inhibitor LY294002 partially reversed the effects of protein 4.1 R knockdown on melanoma cells. In conclusion, these findings suggest that protein 4.1 R may negatively regulate melanoma progression through mechanisms associated with glycolytic remodeling and PI3K/AKT/mTOR signaling.