Transcriptome profiling analysis reveals that ATP6V0E2 is involved in the lysosomal activation by anlotinib

• Published in: Cell death & disease 2020-08, Vol.11 (8), p.702-702, Article 702
• Main Authors: Sun, Xin, Shu, Yuhan, Yan, Peiyi, Huang, Hongliang, Gao, Ruilan, Xu, Mengting, Lu, Liqin, Tian, Jingkui, Huang, Dongsheng, Zhang, Jianbin
• Format: Article
• Language: English
• Subjects: 13/51; 14/19; 38/91; 42/41; 631/67/1059/602; 631/80/39/2346; 96/95; Adenosine triphosphatase; Angiogenesis; Animals; Antibodies; Apoptosis; Apoptosis - drug effects; Autophagosomes - metabolism; Autophagy; Autophagy - drug effects; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - genetics; Biochemistry; Biomedical and Life Sciences; Carcinoma, Non-Small-Cell Lung - metabolism; Cell Biology; Cell Culture; Cell death; Cell Line, Tumor; Cell Nucleus - metabolism; Colon cancer; Colonic Neoplasms - drug therapy; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Colorectal cancer; Enzyme inhibitors; Gene expression; Gene Expression Profiling - methods; Humans; Immunology; Indoles - metabolism; Indoles - pharmacology; Life Sciences; Lung Neoplasms - metabolism; Lysosomes; Lysosomes - drug effects; Lysosomes - metabolism; Male; Mechanistic Target of Rapamycin Complex 1 - metabolism; Mice; Mice, Inbred BALB C; Non-small cell lung carcinoma; Nuclear transport; Organelles; Phagocytosis; Phagosomes; Protein Transport - drug effects; Protein-tyrosine kinase receptors; Quinolines - metabolism; Quinolines - pharmacology; Rapamycin; Reactive oxygen species; Receptor Protein-Tyrosine Kinases; Signal Transduction - drug effects; TOR protein; TOR Serine-Threonine Kinases - metabolism; Transcriptome - genetics; Transcriptomes; Tumor suppression
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-020-02904-0

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.