Autophagy Inhibition Potentiates the Anti-angiogenic Property of Multikinase Inhibitor Anlotinib through JAK2/STAT3/VEGFA Signaling in Non-small Cell Lung Cancer Cells
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BACKGROUND: The efficacy and safety of multikinase inhibitor anlotinib have been confirmed in the treatment of advanced non-small cell lung cancer (NSCLC). However, the direct functional mechanisms of tumor lethality mediated by anlotinib were not fully elucidated, and the underlying mechanisms related to resistance remain largely elusive. METHODS: Cell viability, colony formation, apoptosis and tumor growth assays were performed to examine the effect of anlotinib on lung cancer cells in vitro and in vivo. The punctate patterns of LC3-I/II were detected by confocal microscopy. HUVECs motility was detected using Transwell and scratch wound-healing assay. To visualize the microvessels, tubular formation assay was performed. The expression of LC3-I/II and beclin-1 and the changes of JAK2/STAT3/VEGFA pathway were detected by western blotting. The VEGFA levels in tumor supernatant were measured by ELISA. RESULTS: Anlotinib treatment decreased cell viability and induced apoptosis in Calu-1 and A549 cells. Moreover, anlotinib induced human lung cancer cell autophagy in a dose- and time-dependent manner. Blocking autophagy enhanced the cytotoxicity and anti-angiogenic ability of anlotinib as evidenced by HUVECs migration, invasion, and tubular formation assay. Co-administration of anlotinib and chloroquine (CQ) further reduced VEGFA level in the tumor supernatant, compared with that of anlotinib or CQ treatment alone. When autophagy was induced by rapamycin, the JAK2/STAT3 pathway was activated and VEGFA was elevated, which was attenuated after deactivating STAT3 by S3I-201. Further in vivo studies showed that anlotinib inhibited tumor growth, induced autophagy and suppressed JAK2/STAT3/VEGFA pathway, and CQ enhanced this effect. CONCLUSION: Anlotinib induced apoptosis and protective autophagy in human lung cancer cell lines. Autophagy inhibition further enhanced the cytotoxic effects of anlotinib, and potentiated the anti-angiogenic property of anlotinib through JAK2/STAT3/VEGFA signaling.
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Metabolic adaptation has a remarkable role in maintaining or supporting the survival of cancer stem- or dormant cells.
“Metabolic adaptation also has a remarkable role in maintaining/supporting the survival of the so-called cancer stem- or dormant cells [96, 97].”
From Hypoxia Signaling in Cancer: From Basics to Clinical Practice (2021) · cites this paper as [97]
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References 35 · Cited by 187
- Authors
- Liang, L., Hui, K., Hu, C., Wen, Y., Yang, S., Zhu, P., Wang, L., Xia, Y., Qiao, Y., Sun, W., Fei, J., Chen, T., Zhao, F., Yang, B., & Jiang, X.
- Affiliations
- Xuzhou Medical College (CN)
- National Health and Family Planning Commission (CN)
- Corresponding author
- Jiang, Xiaodong
- ORCID
- Venue
- Journal of Experimental & Clinical Cancer Research
- Published
- 2019-02-12
- Volume
- 38
- Issue
- 1
- Pages
- 71-71
- ISSN
- 0392-9078 (ISSN-L)
- 1756-9966
- PMC
- PMC6373028
- OpenAlex
- W2922410525
- Cited by
- 187
- References
- 35
- Citations by year
- 2026: 10 · 2025: 21 · 2024: 34 · 2023: 35 · 2022: 32 · 2021: 29 · 2020: 21 · 2019: 3 · 2018: 1
- FWCI
- 16.18
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Experimental & Clinical Cancer Research (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (81472792)
- Postgraduate Research & Practice Innovation Program of Jiangsu Province (SJCX18_0707)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- anlotinib, autophagy, non-small cell lung cancer, angiogenesis inhibition, multikinase inhibitor, chloroquine, rapamycin, S3I-201, LC3, Beclin-1, apoptosis, VEGF-A, drug resistance, combination therapy
- MeSH terms
- Animals, Autophagy, Carcinoma, Non-Small-Cell Lung, Disease Models, Animal, Humans, Indoles, Lung Neoplasms, Mice, Nude, Quinolines, Signal Transduction, Xenograft Model Antitumor Assays, Vascular Endothelial Growth Factor A, Cell Line, Tumor, Cell Proliferation, Mice, Janus Kinase 2
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