首页|Pyrimethamine upregulates BNIP3 to interfere SNARE-mediated autophagosome-lysosomal fusion in hepatocellular carcinoma

Pyrimethamine upregulates BNIP3 to interfere SNARE-mediated autophagosome-lysosomal fusion in hepatocellular carcinoma

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  • 国家科技期刊平台
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  • NSTL
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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.

PyrimethamineBNIP3SNAREAutophagosome-lysosome fusionHepatocellular carcinomaSorafenib

Jingjing Wang、Qi Su、Kun Chen、Qing Wu、Jiayan Ren、Wenjuan Tang、Yu Hu、Zeren Zhu、Cheng Cheng、Kaihui Tu、Huaizhen He、Yanmin Zhang

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School of Pharmacy,Health Science Center,Xi'an Jiaotong University,Xi'an,710061,China

国家自然科学基金the"Young Talent Support Plan"of Xi'an Jiaotong UniversityShaanxi Province Science and Technology Development Plan ProjectProject of Shaanxi Provincial Administration ofTraditional Chinese MedicineShaanxi Province Science Fund for Distinguished Young Scholars

819036432022ZDLSF05-052021-03-ZZ-0022023-JC-JQ-59

2024

10.1016/j.jpha.2023.05.014

药物分析学报(英文)
西安交通大学

药物分析学报(英文)

影响因子：0.244
ISSN：2095-1779
年,卷(期)：2024.14(2)
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