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Kayadiol exerted anticancer effects through p53-mediated ferroptosis in NKTCL cells

BACKGROUND: Extranodal natural killer/T cell lymphoma (NKTCL) is a highly aggressive type of non-Hodgkin lymphoma that facing the treatment challenges. Natural compounds are important sources for drug development because of their diverse biological and chemical properties, among which terpenoids hav...

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Autores principales: He, Cuiying, Wang, Chengzhao, Liu, Haisheng, Shan, Baoen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9250166/
https://www.ncbi.nlm.nih.gov/pubmed/35778693
http://dx.doi.org/10.1186/s12885-022-09825-5
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author He, Cuiying
Wang, Chengzhao
Liu, Haisheng
Shan, Baoen
author_facet He, Cuiying
Wang, Chengzhao
Liu, Haisheng
Shan, Baoen
author_sort He, Cuiying
collection PubMed
description BACKGROUND: Extranodal natural killer/T cell lymphoma (NKTCL) is a highly aggressive type of non-Hodgkin lymphoma that facing the treatment challenges. Natural compounds are important sources for drug development because of their diverse biological and chemical properties, among which terpenoids have strong anticancer activities. METHODS: The human NK/T cell lymphoma cell line YT and peripheral blood lymphocytes isolated from NKTCL patients were treated with different concentrations of kayadiol. Then, the following experiments were performed: CCK-8 assay for cell viability, reactive oxygen species (ROS) and glutathione (GSH) assay and co-treatment with NAC, reduced GSH, or ferrostatin-1 for ferroptosis, the proteome profiling for elucidating signaling pathways, and western blot for the expression of p53, SCL7A11, and GPX4. siRNA and CRISPR/Cas9 plasmid for p53 knockout was designed and transfected into YT cells to evaluate the causal role of p53 in kayadiol-induced ferroptosis. The synergistic effect was evaluated by CCK8 assay after co-treatment of kayadiol with L-asparaginase or cisplatin. RESULTS: In this study, we found that kayadiol, a diterpenoid extracted from Torreya nucifera, exerted significant killing effect on NKTCL cells without killing the healthy lymphocytes. Subsequently, we observed that kayadiol treatment triggered significant ferroptosis events, including ROS accumulation and GSH depletion. ROS scavenger NAC, GSH, and ferroptosis inhibitor ferrostatin-1 (Fer-1) reversed kayadiol-induced cell death in NKTCL cells. Furthermore, kayadiol decreased the expression of SLC7A11 and GPX4, the negative regulatory proteins for ferroptosis. We then demonstrated that p53 was the key mediator of kayadiol-induced ferroptosis by SLC7A11/GPX4 axis through p53 knockout experiments. In addition, kayadiol exerted a synergistic effect with L-asparaginase and cisplatin in NKTCL cells. CONCLUSION: Taken together, our results suggested that the natural product kayadiol exerted anticancer effects through p53-mediated ferroptosis in NK/T cell lymphoma cells. Hence, it can serve as an effective alternative in the treatment of NK/T cell lymphoma, especially for patients exhibiting chemoresistance. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12885-022-09825-5.
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spelling pubmed-92501662022-07-03 Kayadiol exerted anticancer effects through p53-mediated ferroptosis in NKTCL cells He, Cuiying Wang, Chengzhao Liu, Haisheng Shan, Baoen BMC Cancer Research BACKGROUND: Extranodal natural killer/T cell lymphoma (NKTCL) is a highly aggressive type of non-Hodgkin lymphoma that facing the treatment challenges. Natural compounds are important sources for drug development because of their diverse biological and chemical properties, among which terpenoids have strong anticancer activities. METHODS: The human NK/T cell lymphoma cell line YT and peripheral blood lymphocytes isolated from NKTCL patients were treated with different concentrations of kayadiol. Then, the following experiments were performed: CCK-8 assay for cell viability, reactive oxygen species (ROS) and glutathione (GSH) assay and co-treatment with NAC, reduced GSH, or ferrostatin-1 for ferroptosis, the proteome profiling for elucidating signaling pathways, and western blot for the expression of p53, SCL7A11, and GPX4. siRNA and CRISPR/Cas9 plasmid for p53 knockout was designed and transfected into YT cells to evaluate the causal role of p53 in kayadiol-induced ferroptosis. The synergistic effect was evaluated by CCK8 assay after co-treatment of kayadiol with L-asparaginase or cisplatin. RESULTS: In this study, we found that kayadiol, a diterpenoid extracted from Torreya nucifera, exerted significant killing effect on NKTCL cells without killing the healthy lymphocytes. Subsequently, we observed that kayadiol treatment triggered significant ferroptosis events, including ROS accumulation and GSH depletion. ROS scavenger NAC, GSH, and ferroptosis inhibitor ferrostatin-1 (Fer-1) reversed kayadiol-induced cell death in NKTCL cells. Furthermore, kayadiol decreased the expression of SLC7A11 and GPX4, the negative regulatory proteins for ferroptosis. We then demonstrated that p53 was the key mediator of kayadiol-induced ferroptosis by SLC7A11/GPX4 axis through p53 knockout experiments. In addition, kayadiol exerted a synergistic effect with L-asparaginase and cisplatin in NKTCL cells. CONCLUSION: Taken together, our results suggested that the natural product kayadiol exerted anticancer effects through p53-mediated ferroptosis in NK/T cell lymphoma cells. Hence, it can serve as an effective alternative in the treatment of NK/T cell lymphoma, especially for patients exhibiting chemoresistance. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12885-022-09825-5. BioMed Central 2022-07-02 /pmc/articles/PMC9250166/ /pubmed/35778693 http://dx.doi.org/10.1186/s12885-022-09825-5 Text en © The Author(s) 2022 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/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
He, Cuiying
Wang, Chengzhao
Liu, Haisheng
Shan, Baoen
Kayadiol exerted anticancer effects through p53-mediated ferroptosis in NKTCL cells
title Kayadiol exerted anticancer effects through p53-mediated ferroptosis in NKTCL cells
title_full Kayadiol exerted anticancer effects through p53-mediated ferroptosis in NKTCL cells
title_fullStr Kayadiol exerted anticancer effects through p53-mediated ferroptosis in NKTCL cells
title_full_unstemmed Kayadiol exerted anticancer effects through p53-mediated ferroptosis in NKTCL cells
title_short Kayadiol exerted anticancer effects through p53-mediated ferroptosis in NKTCL cells
title_sort kayadiol exerted anticancer effects through p53-mediated ferroptosis in nktcl cells
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9250166/
https://www.ncbi.nlm.nih.gov/pubmed/35778693
http://dx.doi.org/10.1186/s12885-022-09825-5
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