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Induction of Ferroptosis by Ophiopogonin-B Through Regulating the Gene Signature AURKA in NSCLC

Ferroptosis is a new type of iron-dependent programmed cell death. In recent years, its role in the diagnosis and treatment of multiple tumors, including non-small cell lung cancer (NSCLC), has been continuously observed. The relationship between the ferroptosis-related genes and the prognosis of pa...

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Autores principales: Li, Liqiu, Gao, Qian, Wang, Jin, Gu, Ling, Li, Zhihui, Zhang, Shiping, Hu, Cheng, He, Menglin, Wang, Yulin, Wang, Zixuan, Yi, Yongxiang, Fu, Jin, Zhang, Xiongfei, Ge, Fei, Chen, Meijuan, Zhang, Xu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9299951/
https://www.ncbi.nlm.nih.gov/pubmed/35875069
http://dx.doi.org/10.3389/fonc.2022.833814
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author Li, Liqiu
Gao, Qian
Wang, Jin
Gu, Ling
Li, Zhihui
Zhang, Shiping
Hu, Cheng
He, Menglin
Wang, Yulin
Wang, Zixuan
Yi, Yongxiang
Fu, Jin
Zhang, Xiongfei
Ge, Fei
Chen, Meijuan
Zhang, Xu
author_facet Li, Liqiu
Gao, Qian
Wang, Jin
Gu, Ling
Li, Zhihui
Zhang, Shiping
Hu, Cheng
He, Menglin
Wang, Yulin
Wang, Zixuan
Yi, Yongxiang
Fu, Jin
Zhang, Xiongfei
Ge, Fei
Chen, Meijuan
Zhang, Xu
author_sort Li, Liqiu
collection PubMed
description Ferroptosis is a new type of iron-dependent programmed cell death. In recent years, its role in the diagnosis and treatment of multiple tumors, including non-small cell lung cancer (NSCLC), has been continuously observed. The relationship between the ferroptosis-related genes and the prognosis of patients with NSCLC needs to be clarified. In this study, The Cancer Genome Atlas (TCGA) and the Gene Expression Synthesis database (Gene Expression Omnibus, GEO) were used to build a model of ferroptosis-related differentially expressed genes (DEGs). A total of 101 ferroptosis-related DEGs were screened using R language, and a 12-gene signature was finally established through univariate Cox regression analysis and least absolute shrinkage and selection operator (LASSO)-penalized Cox regression analysis. According to the risk scores, the patients were divided into a high-risk or a low-risk group, with patients in the low-risk group showing better prognosis. AURKA, one of the genes in the 12-gene signature, was found to be highly expressed in tumors. In addition, further study verified AURKA to be a negative regulator of ferroptosis in NSCLC cells. Ophiopogonin B (OP-B) had been reported to induce apoptosis, mitotic catastrophe, and autophagy in NSCLC cells. Herein, proteomic sequencing analysis and OP-B administration revealed the upregulation of AURKA and the downregulation of PHKG2 and SLC7A5 in the 12-gene signature, indicating that OP-B induced ferroptosis in NSCLC. Determination of the concentrations of malondialdehyde (MDA), glutathione (GSH), and intracellular iron and the mitochondrial membrane potential (MMP) confirmed the induction of ferroptosis by OP-B in vitro. Furthermore, transmission electron microscopy (TEM) examination of lung cancer xenotransplantation in nude mice confirmed that OP-B induced ferroptosis in vivo. Further study of the molecular mechanism showed that the ferroptosis effect caused by OP-B can be partially reversed by the overexpression of AURKA. Overall, our study established a new ferroptosis-related risk prediction model for the prognosis of patients with NSCLC, revealed the enrichment pathways of ferroptosis in NSCLC, and discovered the negative regulation of AURKA in ferroptosis. On this basis, we demonstrated that OP-B can induce ferroptosis in NSCLC and clarified the specific molecular mechanism of OP-B inducing ferroptosis by regulating the expression of AURKA.
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spelling pubmed-92999512022-07-21 Induction of Ferroptosis by Ophiopogonin-B Through Regulating the Gene Signature AURKA in NSCLC Li, Liqiu Gao, Qian Wang, Jin Gu, Ling Li, Zhihui Zhang, Shiping Hu, Cheng He, Menglin Wang, Yulin Wang, Zixuan Yi, Yongxiang Fu, Jin Zhang, Xiongfei Ge, Fei Chen, Meijuan Zhang, Xu Front Oncol Oncology Ferroptosis is a new type of iron-dependent programmed cell death. In recent years, its role in the diagnosis and treatment of multiple tumors, including non-small cell lung cancer (NSCLC), has been continuously observed. The relationship between the ferroptosis-related genes and the prognosis of patients with NSCLC needs to be clarified. In this study, The Cancer Genome Atlas (TCGA) and the Gene Expression Synthesis database (Gene Expression Omnibus, GEO) were used to build a model of ferroptosis-related differentially expressed genes (DEGs). A total of 101 ferroptosis-related DEGs were screened using R language, and a 12-gene signature was finally established through univariate Cox regression analysis and least absolute shrinkage and selection operator (LASSO)-penalized Cox regression analysis. According to the risk scores, the patients were divided into a high-risk or a low-risk group, with patients in the low-risk group showing better prognosis. AURKA, one of the genes in the 12-gene signature, was found to be highly expressed in tumors. In addition, further study verified AURKA to be a negative regulator of ferroptosis in NSCLC cells. Ophiopogonin B (OP-B) had been reported to induce apoptosis, mitotic catastrophe, and autophagy in NSCLC cells. Herein, proteomic sequencing analysis and OP-B administration revealed the upregulation of AURKA and the downregulation of PHKG2 and SLC7A5 in the 12-gene signature, indicating that OP-B induced ferroptosis in NSCLC. Determination of the concentrations of malondialdehyde (MDA), glutathione (GSH), and intracellular iron and the mitochondrial membrane potential (MMP) confirmed the induction of ferroptosis by OP-B in vitro. Furthermore, transmission electron microscopy (TEM) examination of lung cancer xenotransplantation in nude mice confirmed that OP-B induced ferroptosis in vivo. Further study of the molecular mechanism showed that the ferroptosis effect caused by OP-B can be partially reversed by the overexpression of AURKA. Overall, our study established a new ferroptosis-related risk prediction model for the prognosis of patients with NSCLC, revealed the enrichment pathways of ferroptosis in NSCLC, and discovered the negative regulation of AURKA in ferroptosis. On this basis, we demonstrated that OP-B can induce ferroptosis in NSCLC and clarified the specific molecular mechanism of OP-B inducing ferroptosis by regulating the expression of AURKA. Frontiers Media S.A. 2022-06-28 /pmc/articles/PMC9299951/ /pubmed/35875069 http://dx.doi.org/10.3389/fonc.2022.833814 Text en Copyright © 2022 Li, Gao, Wang, Gu, Li, Zhang, Hu, He, Wang, Wang, Yi, Fu, Zhang, Ge, Chen and Zhang https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Li, Liqiu
Gao, Qian
Wang, Jin
Gu, Ling
Li, Zhihui
Zhang, Shiping
Hu, Cheng
He, Menglin
Wang, Yulin
Wang, Zixuan
Yi, Yongxiang
Fu, Jin
Zhang, Xiongfei
Ge, Fei
Chen, Meijuan
Zhang, Xu
Induction of Ferroptosis by Ophiopogonin-B Through Regulating the Gene Signature AURKA in NSCLC
title Induction of Ferroptosis by Ophiopogonin-B Through Regulating the Gene Signature AURKA in NSCLC
title_full Induction of Ferroptosis by Ophiopogonin-B Through Regulating the Gene Signature AURKA in NSCLC
title_fullStr Induction of Ferroptosis by Ophiopogonin-B Through Regulating the Gene Signature AURKA in NSCLC
title_full_unstemmed Induction of Ferroptosis by Ophiopogonin-B Through Regulating the Gene Signature AURKA in NSCLC
title_short Induction of Ferroptosis by Ophiopogonin-B Through Regulating the Gene Signature AURKA in NSCLC
title_sort induction of ferroptosis by ophiopogonin-b through regulating the gene signature aurka in nsclc
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9299951/
https://www.ncbi.nlm.nih.gov/pubmed/35875069
http://dx.doi.org/10.3389/fonc.2022.833814
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