AMPK/mTOR/ULK1-mediated cytotoxic autophagy synergizes with apoptosis to drive the anti-endometrial cancer efficacy of platinum nanoclusters.

BACKGROUND: The clinical management of endometrial cancer (EC) is frequently hindered by the dose-limiting toxicities and acquired resistance associated with conventional cisplatin. This study aims to evaluate the therapeutic potential and precise intracellular mechanisms of a rationally engineered, highly biocompatible platinum nanocluster (Nano-Pt) in EC. METHODS: Cellular internalization, proliferation, migration, and apoptosis were evaluated in EC cell lines (HEC-1-B, RL95-2) and normal human endometrial epithelial cells (T-HEECs). Dynamic autophagic flux and underlying signaling pathways were assessed using transmission electron microscopy, mRFP-GFP-LC3B adenovirus, and Western blotting. The in vivo anti-tumor efficacy and systemic safety of Nano-Pt were validated utilizing a BALB/c nude mouse xenograft model. RESULTS: Nano-Pt exhibited highly efficient endocytosis, preferentially accumulating in mitochondria and lysosomes. It robustly suppressed EC cell proliferation and migration while demonstrating minimal toxicity to normal cells. Mechanistically, Nano-Pt induced classical mitochondria-mediated apoptosis. Concurrently, it induced noticeable ultrastructural mitochondrial alterations and potentially perturbed intracellular homeostasis, which was associated with the activation of the cellular energy sensor AMPK. This subsequently suppressed mTOR and activated the ULK1 complex, initiating profound autophagic flux. Pharmacological rescue experiments using 3-Methyladenine confirmed that this Nano-Pt-induced autophagy was distinctly cytotoxic, acting synergistically with apoptosis to execute EC cells. In vivo evaluations further demonstrated that Nano-Pt impeded xenograft tumor growth with superior efficacy and a safer preliminary systemic profile compared to cisplatin. CONCLUSION: Nano-Pt exerts potent anti-tumor effects in EC by orchestrating a lethal crosstalk between mitochondria-mediated apoptosis and cytotoxic autophagy via the AMPK/mTOR/ULK1 signaling axis, highlighting its immense potential as a safe and effective nanotherapeutic.