Abstract
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.
Highlights
Anlotinib, a new oral small-molecule receptor tyrosine kinase inhibitor developed by Chia-tai Tianqing Pharmaceutical Co., Ltd. in China, targets VEGFR1
HCT116 or SW480 cells were treated with anlotinib for different time, and we observed that anlotinib treatment led to more cell apoptosis with the time increased (Supplementary Fig. 2c), suggesting a timedependent effect
We sought to investigate the relationship between the lysosome and the therapeutic response to anlotinib in human colon cancer and further explore its possible mechanism, in an attempt to provide clinical therapy choices for colon cancer patients
Summary
A new oral small-molecule receptor tyrosine kinase inhibitor developed by Chia-tai Tianqing Pharmaceutical Co., Ltd. in China, targets VEGFR1 The antitumor effect of anlotinib has been reported in many preclinical and clinical trials[3]. Anlotinib improved both progression-free survival and overall survival in a phase III trial in patients with advanced non-small-cell lung cancer[4,5], despite progression of the cancer after two lines of prior treatments. Anlotinib has been just approved as a third-line treatment for advanced non-small-cell lung cancer patients by the CFDA. A randomized phase IIB trial in patients with advanced soft tissue sarcoma demonstrates that anlotinib significantly extends the median progression-free survival[6,7]. Similar to that of other receptor tyrosine kinase inhibitors, the combined treatment of anlotinib with chemotherapy does not appear to be more beneficial than anlotinib alone[13]
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