Docetaxel enhances lysosomal function through TFEB activation

Jianbin Zhang,Xin Sun,Liqin Lu,Yun Chen,Yin Kwan Wong,Liming Wang,Dongsheng Huang,Han-Ming Shen,Liu Yang,Jigang Wang

doi:10.1038/s41419-018-0571-4

Abstract

Docetaxel is an effective and commonly used chemotherapeutic drug for cancer. Autophagy has been reported to be involved in the anticancer mechanism of docetaxel. However, the effect of docetaxel on lysosomal function remains elusive. In the present study, we first found that docetaxel treatment enhances autophagic flux in different cancer cells. Moreover, docetaxel treatment activates lysosomal function and promotes its fusion with autophagosome. Second, doctaxel treatment activates TFEB (transcription factor EB), a key nuclear transcription factor in control of lysosome biogenesis and function. We found that docetaxel promotes TFEB nuclear translocation and increases its transcriptional activity while knockdown of TFEB impairs lysosomal activation by docetaxel. Thirdly, TFEB activation by docetaxel is mediated by ROS (reactive oxygen species) generation and scavenging of ROS suppresses TFEB activity and lysosomal function in docetaxel-treated cells. Finally, inhibition of lysosomal function leads to increased docetaxel-induced cell death, suggesting that lysosomal activation protects against docetaxel-mediated apoptosis. Taken together, our results provide novel insights into the regulatory mechanisms of docetaxel on lysosomes, which could facilitate the development of novel potential cancer therapeutic agents via lysosomal inhibition.

Highlights

Docetaxel is an effective and commonly used chemotherapeutic drug for cancer
We found that Transcriptional factor EB (TFEB) activation and associated autophagy and lysosomal levels increased rapidly in response to docetaxel treatment in gastric cancer cells
In the human gastric cancer cell line AGS, docetaxel treatment led to an increase in the levels of the commonly used autophagy marker LC3-II (Fig. 1a)

Summary

Introduction

Docetaxel is an effective and commonly used chemotherapeutic drug for cancer. Autophagy has been reported to be involved in the anticancer mechanism of docetaxel. By the time of diagnosis, the majority of patients are already preapplied in a variety of tumors, including advanced gastric cancer, non-small cell lung cancer, hormone-refractory prostate cancer and breast cancer[5,6,7]. The chemotherapeutic potential of PEG-b-PLGA copolymer micelles combining docetaxel and the autophagy inhibitor CQ (chloroquine) has been investigated and the co-delivery micelles have displayed demonstrably superior therapeutic effects against cancer cells than either the free drug or docetaxel-loaded micelles[15]. This result provides a promising combination therapeutic strategy in enhancing the antitumor efficacy of docetaxel

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Results

Conclusion