<br>MK8722 启动早期自噬，同时通过 FASN 依赖性脂质代谢重编程抑制晚期自噬。,Theranostics

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MK8722 启动早期自噬，同时通过 FASN 依赖性脂质代谢重编程抑制晚期自噬。
Theranostics ( IF 12.4 ) Pub Date : 2024-01-01 , DOI: 10.7150/thno.83051
Luhui Wang _{1,

2} , Haiyan Zhu ₃ , Zhehao Shi ₄ , Bo Chen ₅ , Huirong Huang ₆ , Ganglian Lin ₅ , Jiacheng Li ₅ , Haitao Yu ₅ , Shihao Xu ₁ , Gang Chen ₅ , Rongying Ou ₂ , Chunxiu Dai ₇

Affiliation

背景和目的：上皮性卵巢癌（EOC）发病隐匿，预后不良，耐药性是改善这些患者预后的主要问题。癌细胞对大多数化疗药物的耐药性可能与自噬机制有关。本研究旨在评估MK8722（一种激活AMP激活蛋白激酶（AMPK）的小分子化合物）对EOC细胞的治疗效果，并提出治疗EOC的新策略。目的：探讨MK8722对EOC细胞的治疗作用，并阐明其潜在机制。方法与结果：发现MK8722能有效抑制EOC细胞的恶性生物学行为。体外实验表明，MK8722靶向并降低脂质代谢途径相关脂肪酸合酶（FASN）的表达水平，导致脂滴积累。此外，透射电子显微镜显示存在自噬体影响的线粒体。 Western blotting 证实 MK8722 通过 FASN 依赖性脂质代谢重编程，在激活上游自噬 (PI3K/AKT/mTOR) 和抑制下游自噬中发挥作用。质粒瞬时转染证明 MK8722 通过阻断自噬体-溶酶体融合来抑制晚期自噬。免疫荧光和基因沉默表明，这种效应是通过抑制 FASN 与 SNARE 复合物 STX17-SNP29-VAMP8 的相互作用来实现的。此外，利用皮下异种移植小鼠模型验证了MK8722的抗肿瘤作用。结论：研究结果表明，使用 MK8722 可能是治疗 EOC 的新策略，因为它有潜力成为新的自噬/线粒体自噬抑制剂。其作用靶点FASN是脂质代谢与自噬之间的分子串扰，探索FASN的潜在机制可能会提供新的研究方向。

"点击查看英文标题和摘要"

MK8722 initiates early-stage autophagy while inhibiting late-stage autophagy via FASN-dependent reprogramming of lipid metabolism.

Background and objective: Epithelial ovarian cancer (EOC) is associated with latent onset and poor prognosis, with drug resistance being a main concern in improving the prognosis of these patients. The resistance of cancer cells to most chemotherapeutic agents can be related to autophagy mechanisms. This study aimed to assess the therapeutic effect of MK8722, a small-molecule compound that activates AMP-activated protein kinase (AMPK), on EOC cells and to propose a novel strategy for the treatment of EOC. Purpose: To explore the therapeutic effects of MK8722 on EOC cells, and to elucidate the underlying mechanism. Methods and results: It was found that MK8722 effectively inhibited the malignant biological behaviors of EOC cells. In vitro experiments showed that MK8722 targeted and decreased the lipid metabolic pathway-related fatty acid synthase (FASN) expression levels, causing the accumulation of lipid droplets. In addition, transmission electron microscopy revealed the presence of autophagosome-affected mitochondria. Western blotting confirmed that MK8722 plays a role in activating autophagy upstream (PI3K/AKT/mTOR) and inhibiting autophagy downstream via FASN-dependent reprogramming of lipid metabolism. Plasmid transient transfection demonstrated that MK8722 suppressed late-stage autophagy by blocking autophagosome-lysosome fusion. Immunofluorescence and gene silencing revealed that this effect was achieved by inhibiting the interaction of FASN with the SNARE complexes STX17-SNP29-VAMP8. Furthermore, the antitumor effect of MK8722 was verified using a subcutaneous xenograft mouse model. Conclusion: The findings suggest that using MK8722 may be a new strategy for treating EOC, as it has the potential to be a new autophagy/mitophagy inhibitor. Its target of action, FASN, is a molecular crosstalk between lipid metabolism and autophagy, and exploration of the underlying mechanism of FASN may provide a new research direction.

更新日期：2024-01-01

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