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

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

doi:10.1016/j.jpha.2023.05.014

Volume 14 Issue 2

Feb. 2024

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Article Navigation > Journal of Pharmaceutical Analysis > 2024 > 14(2): 211-224

Jingjing Wang, Qi Su, Kun Chen, Qing Wu, Jiayan Ren, Wenjuan Tang, Yu Hu, Zeren Zhu, Cheng Cheng, Kaihui Tu, Huaizhen He, Yanmin Zhang. Pyrimethamine upregulates BNIP3 to interfere SNARE-mediated autophagosome-lysosomal fusion in hepatocellular carcinoma[J]. Journal of Pharmaceutical Analysis, 2024, 14(2): 211-224. doi: 10.1016/j.jpha.2023.05.014

Citation:

Jingjing Wang, Qi Su, Kun Chen, Qing Wu, Jiayan Ren, Wenjuan Tang, Yu Hu, Zeren Zhu, Cheng Cheng, Kaihui Tu, Huaizhen He, Yanmin Zhang. Pyrimethamine upregulates BNIP3 to interfere SNARE-mediated autophagosome-lysosomal fusion in hepatocellular carcinoma[J]. Journal of Pharmaceutical Analysis, 2024, 14(2): 211-224. doi: 10.1016/j.jpha.2023.05.014

Citation:

Jingjing Wang, Qi Su, Kun Chen, Qing Wu, Jiayan Ren, Wenjuan Tang, Yu Hu, Zeren Zhu, Cheng Cheng, Kaihui Tu, Huaizhen He, Yanmin Zhang. Pyrimethamine upregulates BNIP3 to interfere SNARE-mediated autophagosome-lysosomal fusion in hepatocellular carcinoma[J]. Journal of Pharmaceutical Analysis, 2024, 14(2): 211-224. doi: 10.1016/j.jpha.2023.05.014

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

doi: 10.1016/j.jpha.2023.05.014

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

Funds:

This work was 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), the Project of Shaanxi Provincial Administration of Traditional Chinese Medicine (Project No.: 2021-03-ZZ-002), and the Shaanxi Province Science Fund for Distinguished Young Scholars (Grant No: 2023-JC-JQ-59). We also thank Miss Ying Hao of the Instrument Analysis Center of Xi'an Jiaotong University for her assistance with super-resolution confocal microscopy.

Received Date: Apr. 07, 2023
Accepted Date: May 29, 2023
Rev Recd Date: May 13, 2023
Publish Date: Feb. 29, 2024

Abstract

Abstract

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.
- Pyrimethamine,
- BNIP3,
- SNARE,
- Autophagosome-lysosome fusion,
- Hepatocellular carcinoma,
- Sorafenib

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References(51)

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