N6-methyladenosine-modified GPX2 impacts cancer cell stemness and TKI resistance through regulating of redox metabolism
Abstract As a predominant oncogenic driver in non-small cell lung cancer (NSCLC), EGFR frequently undergoes amplification or mutation, with EGFR-tyrosine kinase inhibitors (EGFR-TKIs) like gefitinib and erlotinib constituting frontline therapy for advanced EGFR-mutant cases. However, both primary an...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-06-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07764-0 |
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| author | Xu Yang Long Yu Miaomiao Shao Huiling Yang Kangwei Qi Gaofei He Lanxin Wang Di Kong Jianxin Gu Xiaolin Xu Lan Wang |
| author_facet | Xu Yang Long Yu Miaomiao Shao Huiling Yang Kangwei Qi Gaofei He Lanxin Wang Di Kong Jianxin Gu Xiaolin Xu Lan Wang |
| author_sort | Xu Yang |
| collection | DOAJ |
| description | Abstract As a predominant oncogenic driver in non-small cell lung cancer (NSCLC), EGFR frequently undergoes amplification or mutation, with EGFR-tyrosine kinase inhibitors (EGFR-TKIs) like gefitinib and erlotinib constituting frontline therapy for advanced EGFR-mutant cases. However, both primary and acquired resistance significantly limit clinical efficacy. Here, we revealed that glutathione metabolic pathway controlled by glutathione peroxidase GPX2 was abnormally activated in gefitinib-resistant A549 and HCC827-GR cell lines. Mechanistically, GPX2 triggers Hedgehog signaling activation through releasing GLI transcriptional regulator, promoting cancer stem cell (CSC) characteristics and TKI resistance. Notably, N6-methyladenosine (m6A) modification on GPX2 mRNA mediated by METTL14 diminished its stability. In vivo, GPX2 deletion constrained glutathione metabolism and boosted the effectiveness of TKI in cell line-derived xenograft models. Collectively, these findings demonstrate that GPX2 serves as a positive regulator of both primary and acquired EGFR-TKI resistance and could be a promising therapeutic target for precise treatment of NSCLC. |
| format | Article |
| id | doaj-art-0410b0ee2fe04d00a68776e4f5183f21 |
| institution | OA Journals |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-0410b0ee2fe04d00a68776e4f5183f212025-08-20T02:10:38ZengNature Publishing GroupCell Death and Disease2041-48892025-06-0116111210.1038/s41419-025-07764-0N6-methyladenosine-modified GPX2 impacts cancer cell stemness and TKI resistance through regulating of redox metabolismXu Yang0Long Yu1Miaomiao Shao2Huiling Yang3Kangwei Qi4Gaofei He5Lanxin Wang6Di Kong7Jianxin Gu8Xiaolin Xu9Lan Wang10NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan UniversityNHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan UniversitySchool of Medicine, Nanjing University of Chinese MedicineDepartment of Pathology, The First Affiliated Hospital of Naval Medical UniversityNHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan UniversityNHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan UniversityNHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan UniversityNHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan UniversityNHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan UniversityDepartment of Cardiothoracic Surgery, The Third Affiliated Hospital of Naval Medical UniversityNHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan UniversityAbstract As a predominant oncogenic driver in non-small cell lung cancer (NSCLC), EGFR frequently undergoes amplification or mutation, with EGFR-tyrosine kinase inhibitors (EGFR-TKIs) like gefitinib and erlotinib constituting frontline therapy for advanced EGFR-mutant cases. However, both primary and acquired resistance significantly limit clinical efficacy. Here, we revealed that glutathione metabolic pathway controlled by glutathione peroxidase GPX2 was abnormally activated in gefitinib-resistant A549 and HCC827-GR cell lines. Mechanistically, GPX2 triggers Hedgehog signaling activation through releasing GLI transcriptional regulator, promoting cancer stem cell (CSC) characteristics and TKI resistance. Notably, N6-methyladenosine (m6A) modification on GPX2 mRNA mediated by METTL14 diminished its stability. In vivo, GPX2 deletion constrained glutathione metabolism and boosted the effectiveness of TKI in cell line-derived xenograft models. Collectively, these findings demonstrate that GPX2 serves as a positive regulator of both primary and acquired EGFR-TKI resistance and could be a promising therapeutic target for precise treatment of NSCLC.https://doi.org/10.1038/s41419-025-07764-0 |
| spellingShingle | Xu Yang Long Yu Miaomiao Shao Huiling Yang Kangwei Qi Gaofei He Lanxin Wang Di Kong Jianxin Gu Xiaolin Xu Lan Wang N6-methyladenosine-modified GPX2 impacts cancer cell stemness and TKI resistance through regulating of redox metabolism Cell Death and Disease |
| title | N6-methyladenosine-modified GPX2 impacts cancer cell stemness and TKI resistance through regulating of redox metabolism |
| title_full | N6-methyladenosine-modified GPX2 impacts cancer cell stemness and TKI resistance through regulating of redox metabolism |
| title_fullStr | N6-methyladenosine-modified GPX2 impacts cancer cell stemness and TKI resistance through regulating of redox metabolism |
| title_full_unstemmed | N6-methyladenosine-modified GPX2 impacts cancer cell stemness and TKI resistance through regulating of redox metabolism |
| title_short | N6-methyladenosine-modified GPX2 impacts cancer cell stemness and TKI resistance through regulating of redox metabolism |
| title_sort | n6 methyladenosine modified gpx2 impacts cancer cell stemness and tki resistance through regulating of redox metabolism |
| url | https://doi.org/10.1038/s41419-025-07764-0 |
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