Article

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

Authors: Zhe Li1, Yu-ting Zhu1, Min Xiang2, Jun-lan Qiu3, Shou-qing Luo4, Fang Lin1
1 Department of Pharmacology, Laboratory of Aging and Nervous Diseases (SZS0703), Soochow University School of Pharmaceutical Science, Suzhou 215123, China
2 Suzhou Vocational Health College, Suzhou 215123, China
3 Department of Oncology, The Affiliated Suzhou Science & Technology Town Hospital of Nanjing Medical University, Suzhou 215123, China
4 Peninsula Medical School, University of Plymouth, Research Way, Plymouth PL6 8BU, UK
Correspondence to: Shou-qing Luo: shouqing.luo@plymouth.ac.uk, Fang Lin: bluestonelin@hotmail.com,
DOI: 10.1038/s41401-020-0445-z
Received: 18 December 2019
Accepted: 15 May 2020
Advance online: 23 July 2020

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.
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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