Department of Pharmacology, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Biomedical Engineering Facility of National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
Int J Biol Sci. 2024 Oct 14;20(14):5576-5593. doi: 10.7150/ijbs.96651. eCollection 2024.
Abnormal differentiation of cells is a hallmark of malignancy. Induction of cancer-cell differentiation is emerging as a novel therapeutic strategy with low toxicity in hematological malignances, but whether such treatment can be used in solid tumors is not known. Here, we uncovered a novel function of acetyl coenzyme A acetyltransferase (ACAT1) in regulating the differentiation of glioblastoma (GBM) cells. Inhibition of ACAT1 promoted the differentiation of GBM cells into astrocytes but also delayed tumor growth. Mechanistically, suppression of ACAT1 restored mitochondrial function and led to metabolic "reprogramming" in GBM cells: reduction of fatty-acid oxidation and acetyl-CoA, but an increase in free fatty acids. Importantly, ACAT1 negatively regulated the choline metabolic pathway, which is crucial for the differentiation of GBM cells. Finally, we demonstrated that a naturally available substance, chlorogenic acid (CHA), could inhibit phosphorylation of ACAT1 and so delay GBM progression, CHA is a promising candidate to treat GBM because it could induce the differentiation of cancer cells.
细胞异常分化是恶性肿瘤的一个标志。诱导癌细胞分化作为一种新的治疗策略，在血液恶性肿瘤中具有低毒性，但这种治疗方法是否适用于实体瘤尚不清楚。在这里，我们揭示了乙酰辅酶 A 乙酰转移酶 (ACAT1) 在调节神经胶质瘤 (GBM) 细胞分化中的新功能。抑制 ACAT1 促进了 GBM 细胞向星形胶质细胞分化，但也延迟了肿瘤生长。在机制上，抑制 ACAT1 恢复了线粒体功能，并导致 GBM 细胞发生代谢“重编程”：减少脂肪酸氧化和乙酰辅酶 A，但增加游离脂肪酸。重要的是，ACAT1 负调控胆碱代谢途径，这对 GBM 细胞的分化至关重要。最后，我们证明了一种天然存在的物质，绿原酸 (CHA)，可以抑制 ACAT1 的磷酸化，从而延缓 GBM 的进展，CHA 是治疗 GBM 的一个有前途的候选药物，因为它可以诱导癌细胞分化。
