Alpha-enolase influences ATP pool of cytoplasm and lactate homeostasis by regulating glycolysis in gastric cancer

作者：Xiong Shu, Shiya Liu, Ting Yang, Xuanyu Zhou, Gaigai Shen, Lixin Sun, Long Yu, Yuanting Cao, Yuliang Ran · 发表于：Signal Transduction and Targeted Therapy · 年份：2025 · DOI：10.1038/s41392-025-02451-0 · 被引用次数：13 · 研究领域：Cancer, Hypoxia, and Metabolism、Metabolism, Diabetes, and Cancer、Cancer Research and Treatments

Glycolysis is crucial for maintaining cancer stemness. This study demonstrated the role of the glycolytic enzyme alpha-enolase (ENO1) in glycolysis and stemness in gastric cancer (GC). High ENO1 expression was associated with poor prognosis and promoted malignant phenotypes and stem-like characteristics in patients with GC. Mechanistically, ENO1 directly stimulates lactate and ATP production by regulating glycolysis, affecting lactate homeostasis and intracellular ATP pools, and coregulating the AMPK/mTOR and PI3K/AKT signaling pathways. This ultimately drives GC stemness, epithelial‒mesenchymal transition (EMT)-related marker expression, self-renewal, migration, and invasion. Notably, the increase in the intracellular ATP pool can directly activate the PI3K/AKT pathway in a concentration-dependent manner, thereby further stimulating glycolysis to form a positive feedback loop. The functional role of lactate depends on the simultaneous presence of glycolysis-derived ATP to synergistically activate the PI3K/AKT pathway. Lactate homeostasis can also promote tumor stemness by increasing overall plactylation levels. Furthermore, pharmacological studies revealed that metformin combined with copanlisib significantly inhibited tumors by blocking the energy metabolism pathways PI3K/AKT and AMPK/mTOR. Our findings are the first to reveal the multifaceted role of ENO1 in mediating intracellular signaling and metabolic regulation to enhance stemness in GC. By establishing cell models wi...