Transcriptome profiling analysis reveals that ATP6V0E2 is involved in the lysosomal activation by anlotinib
Transcriptome profiling analysis reveals that ATP6V0E2 is involved in the lysosomal activation by anlotinib
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转录组分析表明 ATP6V0E2 参与安罗替尼的溶酶体激活
DOI：
10.1038/s41419-020-02904-0
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发表时间：
2020-08-24
影响因子：
9
通讯作者：
Zhang，Jianbin
中科院分区：
文献类型：
--
作者：
Sun，Xin;Shu，Yuhan;Zhang，Jianbin
安洛替尼是一种受体酪氨酸激酶抑制剂，具有潜在的抗肿瘤和抗血管生成活性。它已被批准用于治疗非小细胞肺癌。溶酶体是酸性细胞器，参与肿瘤治疗的各种机制。然而，安洛替尼对溶酶体功能的影响尚未被研究。在目前的研究中，安洛替尼诱导人结肠癌细胞的凋亡。通过转录组测序，我们首次发现安洛替尼治疗上调了ATP6V0E2(ATPase H+TransportingV0亚基E2)和其他溶酶体相关基因在人结肠癌中的表达。在人类结肠癌中，我们验证了安洛替尼激活溶酶体功能并促进自噬小体和溶酶体的融合。此外，安洛替尼治疗可抑制mTOR(哺乳动物雷帕霉素靶标)信号，并且安洛替尼对溶酶体功能的激活依赖于mTOR。此外，安洛替尼治疗激活了TFEB，这是一个控制溶酶体生物发生和功能的关键核转录因子。我们发现，安洛替尼治疗促进了TFEB核转位并增强了其转录活性。当TFEB或ATP6V0E2被敲除时，Anlotinib增强的溶酶体功能和自噬作用被减弱。最后，抑制溶酶体功能增强了安洛替尼诱导的细胞死亡和肿瘤抑制，这可能归因于高水平的ROS(活性氧物种)。这些发现表明，溶酶体功能的激活通过调节细胞的氧化还原状态来保护安洛替尼介导的细胞凋亡。综上所述，我们的结果为安洛替尼对溶酶体的调节机制提供了新的见解，这些信息可能有助于开发潜在的抑制溶酶体功能的新型癌症治疗药物。
Anlotinib is a receptor tyrosine kinase inhibitor with potential anti-neoplastic and anti-angiogenic activities. It has been approved for the treatment of non-small-cell lung cancer. Lysosomes are acidic organelles and have been implicated in various mechanisms of cancer therapeutics. However, the effect of anlotinib on lysosomal function has not been investigated. In the present study, anlotinib induces apoptosis in human colon cancer cells. Through transcriptome sequencing, we found for the first time that anlotinib treatment upregulates ATP6V0E2 (ATPase H+Transporting V0 Subunit E2) and other lysosome-related genes expression in human colon cancer. In human colon cancer, we validated that anlotinib activates lysosomal function and enhances the fusion of autophagosomes and lysosomes. Moreover, anlotinib treatment is shown to inhibit mTOR (mammalian target of rapamycin) signaling and the activation of lysosomal function by anlotinib is mTOR dependent. Furthermore, anlotinib treatment activates TFEB, a key nuclear transcription factor that controls lysosome biogenesis and function. We found that anlotinib treatment promotes TFEB nuclear translocation and enhances its transcriptional activity. When TFEB or ATP6V0E2 are knocked down, the enhanced lysosomal function and autophagy by anlotinib are attenuated. Finally, inhibition of lysosomal function enhances anlotinib-induced cell death and tumor suppression, which may be attributed to high levels of ROS (reactive oxygen species). These findings suggest that the activation of lysosomal function protects against anlotinib-mediated cell apoptosis via regulating the cellular redox status. Taken together, our results provide novel insights into the regulatory mechanisms of anlotinib on lysosomes, and this information could facilitate the development of potential novel cancer therapeutic agents that inhibit lysosomal function.