Gambogenic Acid Suppresses Malignant Progression of Non-Small Cell Lung Cancer via GCH1-Mediated Ferroptosis
<b>Introduction:</b> Non-small cell lung cancer (NSCLC) is a lethal type of lung cancer (LC) with a 5-year survival rate of 19%. Because drug resistance typically develops following chemotherapy, radiotherapy, and immunotherapy, a novel NSCLC therapeutic strategy is urgently demanded. Ga...
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MDPI AG
2025-03-01
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| author | Menghan Wang Jiao Liu Wenxi Yu Jiancang Shao Yang Bao Mingming Jin Qingqing Huang Gang Huang |
| author_facet | Menghan Wang Jiao Liu Wenxi Yu Jiancang Shao Yang Bao Mingming Jin Qingqing Huang Gang Huang |
| author_sort | Menghan Wang |
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| description | <b>Introduction:</b> Non-small cell lung cancer (NSCLC) is a lethal type of lung cancer (LC) with a 5-year survival rate of 19%. Because drug resistance typically develops following chemotherapy, radiotherapy, and immunotherapy, a novel NSCLC therapeutic strategy is urgently demanded. Gambogenic acid (GNA), a major bioactive ingredient isolated from gamboge, has multipotent antitumor effects, although activity against NSCLC is unknown. <b>Methods:</b> CCK8, ethynyl deoxyuridine (EdU), the plate colony formation assay, and the transwell and wound healing (WH) assay were used to study the effect of GNA on the proliferation and migration ability of NSCLC. Flow cytometry was used to detect apoptosis and the cell cycle. Proteomic analysis and LiP-SMap were used to detect the downstream target of GNA. Ferroptosis inhibitor ferrostatin-1 was used to detect the effect of GNA on NSCLC ferroptosis. Overexpressing GCH1 was used for a rescue experiment. Subcutaneous tumor and pulmonary metastasis in a mouse model were used to study the effect of GNA on NSCLC growth and metastasis. <b>Results:</b> The results of the present study showed that GNA inhibited the proliferation and migration of NSCLC cells in a dose- and time-dependent manner, which arrested the cell cycle in the G0/G1 phase. In vivo data revealed that GNA inhibited tumor growth and lung metastasis. Proteomic analysis found that GNA significantly inhibited the expression of GTP cyclohydrolase 1 (GCH1). LiP-SMap analysis showed that GNA interacted with ILE248 and ARG249 of GCH1. GCH1 overexpression had a similar role to the ferroptosis inhibitor ferrostatin-1 and restored cell proliferation and migration after GNA treatment. Also, GNA promoted reactive oxygen species (ROS) accumulation, which reduced mitochondrial membrane potential. GCH1 overexpression or ferrostatin-1 treatment reversed GNA regulation of ROS accumulation and mitochondrial membrane potential inhibition. <b>Conclusions:</b> Taken together, these findings confirmed that GNA suppressed the malignant progression of NSCLC by inducing GCH1-mediated ferroptosis. |
| format | Article |
| id | doaj-art-bcf75fa563d5488ea9852f0cd48b0437 |
| institution | DOAJ |
| issn | 1424-8247 |
| language | English |
| publishDate | 2025-03-01 |
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| spelling | doaj-art-bcf75fa563d5488ea9852f0cd48b04372025-08-20T02:42:24ZengMDPI AGPharmaceuticals1424-82472025-03-0118337410.3390/ph18030374Gambogenic Acid Suppresses Malignant Progression of Non-Small Cell Lung Cancer via GCH1-Mediated FerroptosisMenghan Wang0Jiao Liu1Wenxi Yu2Jiancang Shao3Yang Bao4Mingming Jin5Qingqing Huang6Gang Huang7Graduate School of Shanghai University of Traditional Chinese Medicine, Shanghai 201203, ChinaGraduate School of Shanghai University of Traditional Chinese Medicine, Shanghai 201203, ChinaGraduate School of Shanghai University of Traditional Chinese Medicine, Shanghai 201203, ChinaShanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai 201318, ChinaShanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai 201318, ChinaShanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai 201318, ChinaShanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai 201318, ChinaGraduate School of Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China<b>Introduction:</b> Non-small cell lung cancer (NSCLC) is a lethal type of lung cancer (LC) with a 5-year survival rate of 19%. Because drug resistance typically develops following chemotherapy, radiotherapy, and immunotherapy, a novel NSCLC therapeutic strategy is urgently demanded. Gambogenic acid (GNA), a major bioactive ingredient isolated from gamboge, has multipotent antitumor effects, although activity against NSCLC is unknown. <b>Methods:</b> CCK8, ethynyl deoxyuridine (EdU), the plate colony formation assay, and the transwell and wound healing (WH) assay were used to study the effect of GNA on the proliferation and migration ability of NSCLC. Flow cytometry was used to detect apoptosis and the cell cycle. Proteomic analysis and LiP-SMap were used to detect the downstream target of GNA. Ferroptosis inhibitor ferrostatin-1 was used to detect the effect of GNA on NSCLC ferroptosis. Overexpressing GCH1 was used for a rescue experiment. Subcutaneous tumor and pulmonary metastasis in a mouse model were used to study the effect of GNA on NSCLC growth and metastasis. <b>Results:</b> The results of the present study showed that GNA inhibited the proliferation and migration of NSCLC cells in a dose- and time-dependent manner, which arrested the cell cycle in the G0/G1 phase. In vivo data revealed that GNA inhibited tumor growth and lung metastasis. Proteomic analysis found that GNA significantly inhibited the expression of GTP cyclohydrolase 1 (GCH1). LiP-SMap analysis showed that GNA interacted with ILE248 and ARG249 of GCH1. GCH1 overexpression had a similar role to the ferroptosis inhibitor ferrostatin-1 and restored cell proliferation and migration after GNA treatment. Also, GNA promoted reactive oxygen species (ROS) accumulation, which reduced mitochondrial membrane potential. GCH1 overexpression or ferrostatin-1 treatment reversed GNA regulation of ROS accumulation and mitochondrial membrane potential inhibition. <b>Conclusions:</b> Taken together, these findings confirmed that GNA suppressed the malignant progression of NSCLC by inducing GCH1-mediated ferroptosis.https://www.mdpi.com/1424-8247/18/3/374gambogenic acidnon-small cell lung cancerferroptosisGCH1 |
| spellingShingle | Menghan Wang Jiao Liu Wenxi Yu Jiancang Shao Yang Bao Mingming Jin Qingqing Huang Gang Huang Gambogenic Acid Suppresses Malignant Progression of Non-Small Cell Lung Cancer via GCH1-Mediated Ferroptosis Pharmaceuticals gambogenic acid non-small cell lung cancer ferroptosis GCH1 |
| title | Gambogenic Acid Suppresses Malignant Progression of Non-Small Cell Lung Cancer via GCH1-Mediated Ferroptosis |
| title_full | Gambogenic Acid Suppresses Malignant Progression of Non-Small Cell Lung Cancer via GCH1-Mediated Ferroptosis |
| title_fullStr | Gambogenic Acid Suppresses Malignant Progression of Non-Small Cell Lung Cancer via GCH1-Mediated Ferroptosis |
| title_full_unstemmed | Gambogenic Acid Suppresses Malignant Progression of Non-Small Cell Lung Cancer via GCH1-Mediated Ferroptosis |
| title_short | Gambogenic Acid Suppresses Malignant Progression of Non-Small Cell Lung Cancer via GCH1-Mediated Ferroptosis |
| title_sort | gambogenic acid suppresses malignant progression of non small cell lung cancer via gch1 mediated ferroptosis |
| topic | gambogenic acid non-small cell lung cancer ferroptosis GCH1 |
| url | https://www.mdpi.com/1424-8247/18/3/374 |
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