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

Luhui Wang, Haiyan Zhu, Zhehao Shi, Bo Chen, Huirong Huang, Ganglian Lin, Jiacheng Li, Haitao Yu, Shihao Xu, Gang Chen, Rongying Ou, Chunxiu Dai

Theranostics 2024

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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. © The author(s).

Citation

Luhui Wang, Haiyan Zhu, Zhehao Shi, Bo Chen, Huirong Huang, Ganglian Lin, Jiacheng Li, Haitao Yu, Shihao Xu, Gang Chen, Rongying Ou, Chunxiu Dai. MK8722 initiates early-stage autophagy while inhibiting late-stage autophagy via FASN-dependent reprogramming of lipid metabolism. Theranostics. 2024;14(1):75-95