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Apatinib Promotes Ferroptosis in Colorectal Cancer Cells by Targeting ELOVL6/ACSL4 Signaling

BACKGROUND: Colorectal cancer (CRC) is a common digestive system malignancy. Ferroptosis, a new form of regulated cell death, plays a vital role in the pathogenesis and therapy of cancers. OBJECTIVE: We aimed to study the role of apatinib in ferroptosis of CRC cells and its potential mechanisms. MAT...

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Autores principales: Tian, Xiangyang, Li, Shuyuan, Ge, Guoyan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884947/
https://www.ncbi.nlm.nih.gov/pubmed/33603479
http://dx.doi.org/10.2147/CMAR.S274631
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author Tian, Xiangyang
Li, Shuyuan
Ge, Guoyan
author_facet Tian, Xiangyang
Li, Shuyuan
Ge, Guoyan
author_sort Tian, Xiangyang
collection PubMed
description BACKGROUND: Colorectal cancer (CRC) is a common digestive system malignancy. Ferroptosis, a new form of regulated cell death, plays a vital role in the pathogenesis and therapy of cancers. OBJECTIVE: We aimed to study the role of apatinib in ferroptosis of CRC cells and its potential mechanisms. MATERIALS AND METHODS: Human CRC HCT116 cells were exposed to apatinib. Cell viability was examined using a CCK-8 kit. The concentrations of intracellular iron and reactive oxygen species (ROS) were detected using kits. Additionally, Western blot analysis was used to determine the expression of ferroptosis-related proteins. Elongation of very long-chain fatty acids family member 6 (ELOVL6) was one of the targets of apatinib predicted by SwissTargetPrediction. Therefore, ELOVL6 expression was evaluated after treatment with apatinib. Subsequently, the effects of ELOVL6 overexpression on ferroptosis of HCT116 cells were investigated. Finally, STRING database was applied to predict the potential proteins interacting with ELOVL6, and co-immunoprecipitation (co-IP) assay was applied for confirmation. RESULTS: Results indicated that apatinib decreased cell viability and increased the contents of intracellular iron ROS. Moreover, significantly upregulated ACSL4 expression was observed, accompanied by notable downregulation of GPx4 and FTH1 expression after apatinib exposure. Furthermore, ELOVL6 expression was remarkably enhanced in HCT116 cells, which was dramatically inhibited under apatinib intervention. ELOVL6 overexpression reversed the effects of apatinib on cell viability and ferroptosis of HCT116 cells. Moreover, ACSL4, a vital regulator of ferroptosis, could interact with ELOVL6 directly, which was confirmed by the result of co-IP. CONCLUSION: These findings demonstrated that apatinib promoted ferroptosis in CRC cells by targeting ELOVL6/ACSL4, providing a new mechanism support for apatinib application in the clinical treatment of CRC.
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spelling pubmed-78849472021-02-17 Apatinib Promotes Ferroptosis in Colorectal Cancer Cells by Targeting ELOVL6/ACSL4 Signaling Tian, Xiangyang Li, Shuyuan Ge, Guoyan Cancer Manag Res Original Research BACKGROUND: Colorectal cancer (CRC) is a common digestive system malignancy. Ferroptosis, a new form of regulated cell death, plays a vital role in the pathogenesis and therapy of cancers. OBJECTIVE: We aimed to study the role of apatinib in ferroptosis of CRC cells and its potential mechanisms. MATERIALS AND METHODS: Human CRC HCT116 cells were exposed to apatinib. Cell viability was examined using a CCK-8 kit. The concentrations of intracellular iron and reactive oxygen species (ROS) were detected using kits. Additionally, Western blot analysis was used to determine the expression of ferroptosis-related proteins. Elongation of very long-chain fatty acids family member 6 (ELOVL6) was one of the targets of apatinib predicted by SwissTargetPrediction. Therefore, ELOVL6 expression was evaluated after treatment with apatinib. Subsequently, the effects of ELOVL6 overexpression on ferroptosis of HCT116 cells were investigated. Finally, STRING database was applied to predict the potential proteins interacting with ELOVL6, and co-immunoprecipitation (co-IP) assay was applied for confirmation. RESULTS: Results indicated that apatinib decreased cell viability and increased the contents of intracellular iron ROS. Moreover, significantly upregulated ACSL4 expression was observed, accompanied by notable downregulation of GPx4 and FTH1 expression after apatinib exposure. Furthermore, ELOVL6 expression was remarkably enhanced in HCT116 cells, which was dramatically inhibited under apatinib intervention. ELOVL6 overexpression reversed the effects of apatinib on cell viability and ferroptosis of HCT116 cells. Moreover, ACSL4, a vital regulator of ferroptosis, could interact with ELOVL6 directly, which was confirmed by the result of co-IP. CONCLUSION: These findings demonstrated that apatinib promoted ferroptosis in CRC cells by targeting ELOVL6/ACSL4, providing a new mechanism support for apatinib application in the clinical treatment of CRC. Dove 2021-02-11 /pmc/articles/PMC7884947/ /pubmed/33603479 http://dx.doi.org/10.2147/CMAR.S274631 Text en © 2021 Tian et al. http://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).
spellingShingle Original Research
Tian, Xiangyang
Li, Shuyuan
Ge, Guoyan
Apatinib Promotes Ferroptosis in Colorectal Cancer Cells by Targeting ELOVL6/ACSL4 Signaling
title Apatinib Promotes Ferroptosis in Colorectal Cancer Cells by Targeting ELOVL6/ACSL4 Signaling
title_full Apatinib Promotes Ferroptosis in Colorectal Cancer Cells by Targeting ELOVL6/ACSL4 Signaling
title_fullStr Apatinib Promotes Ferroptosis in Colorectal Cancer Cells by Targeting ELOVL6/ACSL4 Signaling
title_full_unstemmed Apatinib Promotes Ferroptosis in Colorectal Cancer Cells by Targeting ELOVL6/ACSL4 Signaling
title_short Apatinib Promotes Ferroptosis in Colorectal Cancer Cells by Targeting ELOVL6/ACSL4 Signaling
title_sort apatinib promotes ferroptosis in colorectal cancer cells by targeting elovl6/acsl4 signaling
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884947/
https://www.ncbi.nlm.nih.gov/pubmed/33603479
http://dx.doi.org/10.2147/CMAR.S274631
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