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Enhanced lysosomal function is critical for paclitaxel resistance in cancer cells: reversed by artesunate

Abstract

The mechanism underlying the resistance of cancer cells to chemotherapeutic drug varies with different cancer cells. Recent evidence shows that lysosomal function is associated with drug resistance of cancer cells. Artesunate, a derivative of artemisinin, displays broad antitumor activity and direct cytotoxicity on various tumor cells. Our previous study shows that artesunate increases autophagosome accumulation, while significantly decreases autolysosome number in cancer cells, suggesting that artesunate might impair the lysosomal function. In this study, we investigated the effects of artesunate on lysosomal function and its relationship with chemotherapeutic drug resistance in cancer cells. We found that the lysosomal function was significantly enhanced in two drug-resistant (A549/TAX and A549/DDP) cells. Furthermore, we showed that the enhanced lysosomal function by overexpression of transcription factor EB (TFEB) significantly increased MCF-7 cells resistance to doxorubicin (DOX), whereas the decreased lysosomal function by TFEB-knockdown or lysosome inhibitor chloroquine increased MCF-7 cells sensitivity to DOX. Treatment of A549/TAX cells with artesunate (2.5–50 μM) dose-dependently inhibited lysosomal function and the clearance of dysfunctional mitochondria, and induced cell apoptosis. Moreover, we demonstrated that artesunate exerted more potent inhibition on the resistant (A549/TAX and MCF-7/ADR) cells with higher activity of lysosomal function. Our results suggest that artesunate or other inhibitors of lysosomal function would be potential in the treatment of cancer cells with drug resistance caused by the enhanced lysosomal function.

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Fig. 1: The activity of lysosomal cathepsins is enhanced in paclitaxel-resistant cancer cells.
Fig. 2: The transcription factor EB promotes the tolerance of cells after drug treatment.
Fig. 3: Artesunate inhibits the activity of cathepsins in MCF-7 cells.
Fig. 4: Artesunate inhibits the function of lysosomes in A549/TAX cells in a dose-dependent manner.
Fig. 5: Inhibition of lysosomal function enhances the cytotoxicity induced by artesunate in A549/TAX cells.
Fig. 6: Artesunate inhibits cell proliferation by inhibiting lysosomal function partly through ROS.

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Acknowledgements

This work was supported by grants from the Natural Science Foundation of Jiangsu Province (No. BK20151233), the Scientific and Technological Innovation Team Building Program of Suzhou Vocational Health College (SZWZYTD201801), the Youth Project of Health and Family Planning Bureau of Suzhou New District (No. 2017Q005), Suzhou industrial technology innovation (No. SYSD2016062), the Priority Academic Program Development of the Jiangsu Higher Education Institutes (PAPD).

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ZL completed most of the research work; YTZ and MX performed some research work and wrote the paper. JLQ provided suggestions for the research. SQL and FL designed the research work and revised the paper.

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Correspondence to Shou-qing Luo or Fang Lin.

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The authors declare no competing interests.

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Li, Z., Zhu, Yt., Xiang, M. et al. Enhanced lysosomal function is critical for paclitaxel resistance in cancer cells: reversed by artesunate. Acta Pharmacol Sin 42, 624–632 (2021). https://doi.org/10.1038/s41401-020-0445-z

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Keywords

  • artesunate
  • cisplatin-resistant human lung adenocarcinoma cells (A549/DDP)
  • paclitaxel-resistant human lung adenocarcinoma cells (A549/TAX)
  • doxorubicin-resistant human breast cancer cells (MCF-7/ADR)
  • lysosome
  • TFEB

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