Hepatocellular carcinoma (HCC) is one of the most common tumor types and remains a major clinical challenge. Increasing evidence has revealed that mitophagy inhibitors can enhance the effect of chemotherapy on HCC. Ho...Hepatocellular carcinoma (HCC) is one of the most common tumor types and remains a major clinical challenge. Increasing evidence has revealed that mitophagy inhibitors can enhance the effect of chemotherapy on HCC. However, few mitophagy inhibitors have been approved for clinical use in humans. Pyrimethamine (Pyr) is used to treat infections caused by protozoan parasites. Recent studies have reported that Pyr may be beneficial in the treatment of various tumors. However, its mechanism of action is still not clearly defined. Here, we found that blocking mitophagy sensitized cells to Pyr-induced apoptosis. Mechanistically, Pyr potently induced the accumulation of autophagosomes by inhibiting autophagosome-lysosome fusion in human HCC cells. In vitro and in vivo studies revealed that Pyr blocked autophagosome-lysosome fusion by upregulating BNIP3 to inhibit synaptosomal-associated protein 29 (SNAP29)-vesicle-associated membrane protein 8 (VAMP8) interaction. Moreover, Pyr acted synergistically with sorafenib (Sora) to induce apoptosis and inhibit HCC proliferation in vitro and in vivo. Pyr enhances the sensitivity of HCC cells to Sora, a common chemotherapeutic, by inhibiting mitophagy. Thus, these results provide new insights into the mechanism of action of Pyr and imply that Pyr could potentially be further developed as a novel mitophagy inhibitor. Notably, Pyr and Sora combination therapy could be a promising treatment for malignant HCC.展开更多
Macroautophagy(hereafter autophagy)is a catabolic process by which autophagosomes arising from an isolation membrane fuse with lysosomes to degrade components in the cytoplasm.Autophagosomelysosome fusion step is one ...Macroautophagy(hereafter autophagy)is a catabolic process by which autophagosomes arising from an isolation membrane fuse with lysosomes to degrade components in the cytoplasm.Autophagosomelysosome fusion step is one of the key steps during the process of macroautophagy.The step is extremely complicated and its detailed mechanisms remain unclear.It consists of two phases:first phase is autophagosome migration phase and second phase is fusion of autophagosomes and lysosomes phase.Recently,various molecules have been reported to be involved in each phase.In the first phase,microtubules and actin remodeling mechanism are involved.In the second phase,soluble N-ethylmaleimide-sensitive factor attachment protein receptor(SNARE)proteins,Rab family proteins,phosphoinositide 3-kinase(PI3K)complex and Rubicon are involved.In the present review,we introduce recent findings related to autophagosome-lysosome fusion step and discuss liver diseases possibly associated with autophagosome-lysosome fusion dysfunction.展开更多
基金supported by the National Natural Science Foundation of China(Grant No:81903643)the“Young Talent Support Plan”of Xi'an Jiaotong University,the Shaanxi Province Science and Technology Development Plan Project(Grant No.:2022ZDLSF05-05)+1 种基金the Project of Shaanxi Provincial Administration of Traditional Chinese Medicine(Project No.:2021-03-ZZ-002)the Shaanxi Province Science Fund for Distinguished Young Scholars(Grant No:2023-JC-JQ-59).
文摘Hepatocellular carcinoma (HCC) is one of the most common tumor types and remains a major clinical challenge. Increasing evidence has revealed that mitophagy inhibitors can enhance the effect of chemotherapy on HCC. However, few mitophagy inhibitors have been approved for clinical use in humans. Pyrimethamine (Pyr) is used to treat infections caused by protozoan parasites. Recent studies have reported that Pyr may be beneficial in the treatment of various tumors. However, its mechanism of action is still not clearly defined. Here, we found that blocking mitophagy sensitized cells to Pyr-induced apoptosis. Mechanistically, Pyr potently induced the accumulation of autophagosomes by inhibiting autophagosome-lysosome fusion in human HCC cells. In vitro and in vivo studies revealed that Pyr blocked autophagosome-lysosome fusion by upregulating BNIP3 to inhibit synaptosomal-associated protein 29 (SNAP29)-vesicle-associated membrane protein 8 (VAMP8) interaction. Moreover, Pyr acted synergistically with sorafenib (Sora) to induce apoptosis and inhibit HCC proliferation in vitro and in vivo. Pyr enhances the sensitivity of HCC cells to Sora, a common chemotherapeutic, by inhibiting mitophagy. Thus, these results provide new insights into the mechanism of action of Pyr and imply that Pyr could potentially be further developed as a novel mitophagy inhibitor. Notably, Pyr and Sora combination therapy could be a promising treatment for malignant HCC.
基金This study is partially supported by Japan MEXT KAKENHI to T.Takehara(18H02795)and by The Japanese Society of Gastroenterology to H.Hikita.
文摘Macroautophagy(hereafter autophagy)is a catabolic process by which autophagosomes arising from an isolation membrane fuse with lysosomes to degrade components in the cytoplasm.Autophagosomelysosome fusion step is one of the key steps during the process of macroautophagy.The step is extremely complicated and its detailed mechanisms remain unclear.It consists of two phases:first phase is autophagosome migration phase and second phase is fusion of autophagosomes and lysosomes phase.Recently,various molecules have been reported to be involved in each phase.In the first phase,microtubules and actin remodeling mechanism are involved.In the second phase,soluble N-ethylmaleimide-sensitive factor attachment protein receptor(SNARE)proteins,Rab family proteins,phosphoinositide 3-kinase(PI3K)complex and Rubicon are involved.In the present review,we introduce recent findings related to autophagosome-lysosome fusion step and discuss liver diseases possibly associated with autophagosome-lysosome fusion dysfunction.
