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Lenvatinib inhibits intrahepatic cholangiocarcinoma via Gadd45a-mediated cell cycle arrest

PURPOSE: To evaluate the anticancer activities of lenvatinib in ICC and its possible molecular mechanisms. METHODS: Patients-derived xenograft (PDX) model and cell line-derived xenograft (CDX) model were both used for the in vivo study. For in vivo work, ICC cell lines were applied to analyze the ef...

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Autores principales: Yan, Xia, Wang, Dan, Ning, Zhouyu, Meng, Zhi-qiang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9950313/
https://www.ncbi.nlm.nih.gov/pubmed/36821012
http://dx.doi.org/10.1007/s12672-023-00631-4
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author Yan, Xia
Wang, Dan
Ning, Zhouyu
Meng, Zhi-qiang
author_facet Yan, Xia
Wang, Dan
Ning, Zhouyu
Meng, Zhi-qiang
author_sort Yan, Xia
collection PubMed
description PURPOSE: To evaluate the anticancer activities of lenvatinib in ICC and its possible molecular mechanisms. METHODS: Patients-derived xenograft (PDX) model and cell line-derived xenograft (CDX) model were both used for the in vivo study. For in vivo work, ICC cell lines were applied to analyze the effect of Lenvatinib on cell proliferation, cell cycle progression, apoptosis, and the molecular mechanism. RESULTS: In the present study, we found that lenvatinib dramatically hindered in vivo tumor growth in ICC patient-derived xenograft models. In addition, by using in vitro experiments in ICC cell lines, we found that lenvatinib dose- and time-dependently inhibited the proliferation of ICC cells and induced cell cycle arrest in the G(0)/G(1) phase. Transcriptional profiling analysis further applied indicated that lenvatinib might inhibit cell proliferation through the induction of cell-cycle arrestment via activating of Gadd45a, it was evidenced by that the knockout of Gadd45a significantly attenuated the cycle arrest induced by lenvatinib, as well as the inhibitory effect of lenvatinib on ICC. CONCLUSION: Our work first found that lenvatinib exerted an excellent antitumor effect on ICC, mainly via inducing Gadd45a-mediated cell cycle arrest. Our work provides evidence and a rationale for the future use of lenvatinib in the treatment of ICC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12672-023-00631-4.
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spelling pubmed-99503132023-02-25 Lenvatinib inhibits intrahepatic cholangiocarcinoma via Gadd45a-mediated cell cycle arrest Yan, Xia Wang, Dan Ning, Zhouyu Meng, Zhi-qiang Discov Oncol Research PURPOSE: To evaluate the anticancer activities of lenvatinib in ICC and its possible molecular mechanisms. METHODS: Patients-derived xenograft (PDX) model and cell line-derived xenograft (CDX) model were both used for the in vivo study. For in vivo work, ICC cell lines were applied to analyze the effect of Lenvatinib on cell proliferation, cell cycle progression, apoptosis, and the molecular mechanism. RESULTS: In the present study, we found that lenvatinib dramatically hindered in vivo tumor growth in ICC patient-derived xenograft models. In addition, by using in vitro experiments in ICC cell lines, we found that lenvatinib dose- and time-dependently inhibited the proliferation of ICC cells and induced cell cycle arrest in the G(0)/G(1) phase. Transcriptional profiling analysis further applied indicated that lenvatinib might inhibit cell proliferation through the induction of cell-cycle arrestment via activating of Gadd45a, it was evidenced by that the knockout of Gadd45a significantly attenuated the cycle arrest induced by lenvatinib, as well as the inhibitory effect of lenvatinib on ICC. CONCLUSION: Our work first found that lenvatinib exerted an excellent antitumor effect on ICC, mainly via inducing Gadd45a-mediated cell cycle arrest. Our work provides evidence and a rationale for the future use of lenvatinib in the treatment of ICC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12672-023-00631-4. Springer US 2023-02-23 /pmc/articles/PMC9950313/ /pubmed/36821012 http://dx.doi.org/10.1007/s12672-023-00631-4 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research
Yan, Xia
Wang, Dan
Ning, Zhouyu
Meng, Zhi-qiang
Lenvatinib inhibits intrahepatic cholangiocarcinoma via Gadd45a-mediated cell cycle arrest
title Lenvatinib inhibits intrahepatic cholangiocarcinoma via Gadd45a-mediated cell cycle arrest
title_full Lenvatinib inhibits intrahepatic cholangiocarcinoma via Gadd45a-mediated cell cycle arrest
title_fullStr Lenvatinib inhibits intrahepatic cholangiocarcinoma via Gadd45a-mediated cell cycle arrest
title_full_unstemmed Lenvatinib inhibits intrahepatic cholangiocarcinoma via Gadd45a-mediated cell cycle arrest
title_short Lenvatinib inhibits intrahepatic cholangiocarcinoma via Gadd45a-mediated cell cycle arrest
title_sort lenvatinib inhibits intrahepatic cholangiocarcinoma via gadd45a-mediated cell cycle arrest
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9950313/
https://www.ncbi.nlm.nih.gov/pubmed/36821012
http://dx.doi.org/10.1007/s12672-023-00631-4
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AT mengzhiqiang lenvatinibinhibitsintrahepaticcholangiocarcinomaviagadd45amediatedcellcyclearrest