4HPR nanoformulation regulates MAPKAPK3/3pK signaling to control Bax phosphorylation and mitochondrial translocation to execute apoptosis in neuroblastoma

Abstract

Neuroblastoma (NB) is a neuroendocrine tumor derived from neural crest progenitor cells, commonly arising along the sympathetic nervous system, especially in the adrenal medulla. Despite therapeutic advances, the prognosis for advanced-stage NB remains poor, necessitating improved treatment options. 4HPR has demonstrated cytotoxicity in various tumors, including NB, with low systemic toxicity; however, its clinical use is restricted by poor solubility and bioavailability. To address this, we developed a human serum albumin-based nanoformulation of 4HPR using a simple desolvation method. This formulation effectively induced apoptosis in NB cells, marked by increased ROS generation, elevated Bax/Bcl-2 ratio, and enhanced cell detachment. Notably, we identified for the first time that MAPKAPK3 downregulation leads to reduced Bax phosphorylation and increased mitochondrial translocation. Co-immunoprecipitation confirmed a direct MAPKAPK3–Bax interaction, indicating MAPKAPK3 regulates Bax via phosphorylation. Our nanoformulation modulates this cross-talk, demonstrating promising translational potential as a novel therapeutic strategy for neuroblastoma.