Microsomal glutathione transferase 1 controls metastasis and therapeutic response in melanoma
While recent targeted and immunotherapies in malignant melanoma are encouraging, most patients acquire resistance, implicating a need to identify additional drug targets to improve outcomes. Recently, attention has been given to pathways that regulate redox homeostasis, especially the lipid peroxida...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-10-01
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| Series: | Pharmacological Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661823002554 |
| _version_ | 1827794314256711680 |
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| author | Jie Zhang Zhi-wei Ye Paramita Chakraborty Zhenwu Luo John Culpepper Muhammad Aslam Leilei Zhang Katarina Johansson Jesper Z. Haeggström Jianqiang Xu Magnus Olsson Danyelle M. Townsend Shikhar Mehrotra Ralf Morgenstern Kenneth D. Tew |
| author_facet | Jie Zhang Zhi-wei Ye Paramita Chakraborty Zhenwu Luo John Culpepper Muhammad Aslam Leilei Zhang Katarina Johansson Jesper Z. Haeggström Jianqiang Xu Magnus Olsson Danyelle M. Townsend Shikhar Mehrotra Ralf Morgenstern Kenneth D. Tew |
| author_sort | Jie Zhang |
| collection | DOAJ |
| description | While recent targeted and immunotherapies in malignant melanoma are encouraging, most patients acquire resistance, implicating a need to identify additional drug targets to improve outcomes. Recently, attention has been given to pathways that regulate redox homeostasis, especially the lipid peroxidase pathway that protects cells against ferroptosis. Here we identify microsomal glutathione S-transferase 1 (MGST1), a non-selenium-dependent glutathione peroxidase, as highly expressed in malignant and drug resistant melanomas and as a specific determinant of metastatic spread and therapeutic sensitivity. Loss of MGST1 in mouse and human melanoma enhanced cellular oxidative stress, and diminished glycolysis, oxidative phosphorylation, and pentose phosphate pathway. Gp100 activated pmel-1 T cells killed more Mgst1 KD than control melanoma cells and KD cells were more sensitive to cytotoxic anticancer drugs and ferroptotic cell death. When compared to control, mice bearing Mgst1 KD B16 tumors had more CD8+ T cell infiltration with reduced expression of inhibitory receptors and increased cytokine response, large reduction of lung metastases and enhanced survival. Targeting MGST1 alters the redox balance and limits metastases in melanoma, enhancing the therapeutic index for chemo- and immunotherapies. |
| first_indexed | 2024-03-11T18:31:53Z |
| format | Article |
| id | doaj.art-5d9d42b0e955458aadc407c65b31b648 |
| institution | Directory Open Access Journal |
| issn | 1096-1186 |
| language | English |
| last_indexed | 2024-03-11T18:31:53Z |
| publishDate | 2023-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj.art-5d9d42b0e955458aadc407c65b31b6482023-10-13T11:03:36ZengElsevierPharmacological Research1096-11862023-10-01196106899Microsomal glutathione transferase 1 controls metastasis and therapeutic response in melanomaJie Zhang0Zhi-wei Ye1Paramita Chakraborty2Zhenwu Luo3John Culpepper4Muhammad Aslam5Leilei Zhang6Katarina Johansson7Jesper Z. Haeggström8Jianqiang Xu9Magnus Olsson10Danyelle M. Townsend11Shikhar Mehrotra12Ralf Morgenstern13Kenneth D. Tew14Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC 29425, United States; Corresponding authors.Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC 29425, United StatesDepartment of Surgery, Medical University of South Carolina, Charleston, SC 29425, United StatesDepartment of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, United StatesDepartment of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC 29425, United StatesDepartment of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC 29425, United StatesDepartment of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC 29425, United StatesPfizer Innovation AB, 19190 Sollentuna, SwedenDepartment of Medical Biochemistry and Biophysics, Divisions of Biochemistry and Chemisty 2, Karolinska Institutet, Biomedicum 9A, 17165 Stockholm, SwedenSchool of Life and Pharmaceutical Sciences & Panjin Institute of Industrial Technology (PIIT), Dalian University of Technology, Panjin 124221, ChinaInstitute of Environmental Medicine, Division of Biochemical Toxicology, Karolinska Institutet, 17177 Stockholm, SwedenDepartment of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425, United StatesDepartment of Surgery, Medical University of South Carolina, Charleston, SC 29425, United StatesInstitute of Environmental Medicine, Division of Biochemical Toxicology, Karolinska Institutet, 17177 Stockholm, SwedenDepartment of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC 29425, United States; Corresponding authors.While recent targeted and immunotherapies in malignant melanoma are encouraging, most patients acquire resistance, implicating a need to identify additional drug targets to improve outcomes. Recently, attention has been given to pathways that regulate redox homeostasis, especially the lipid peroxidase pathway that protects cells against ferroptosis. Here we identify microsomal glutathione S-transferase 1 (MGST1), a non-selenium-dependent glutathione peroxidase, as highly expressed in malignant and drug resistant melanomas and as a specific determinant of metastatic spread and therapeutic sensitivity. Loss of MGST1 in mouse and human melanoma enhanced cellular oxidative stress, and diminished glycolysis, oxidative phosphorylation, and pentose phosphate pathway. Gp100 activated pmel-1 T cells killed more Mgst1 KD than control melanoma cells and KD cells were more sensitive to cytotoxic anticancer drugs and ferroptotic cell death. When compared to control, mice bearing Mgst1 KD B16 tumors had more CD8+ T cell infiltration with reduced expression of inhibitory receptors and increased cytokine response, large reduction of lung metastases and enhanced survival. Targeting MGST1 alters the redox balance and limits metastases in melanoma, enhancing the therapeutic index for chemo- and immunotherapies.http://www.sciencedirect.com/science/article/pii/S1043661823002554Microsomal glutathione transferase 1MelanomaFerroptosisOxidative stressRedoxMetastasis |
| spellingShingle | Jie Zhang Zhi-wei Ye Paramita Chakraborty Zhenwu Luo John Culpepper Muhammad Aslam Leilei Zhang Katarina Johansson Jesper Z. Haeggström Jianqiang Xu Magnus Olsson Danyelle M. Townsend Shikhar Mehrotra Ralf Morgenstern Kenneth D. Tew Microsomal glutathione transferase 1 controls metastasis and therapeutic response in melanoma Pharmacological Research Microsomal glutathione transferase 1 Melanoma Ferroptosis Oxidative stress Redox Metastasis |
| title | Microsomal glutathione transferase 1 controls metastasis and therapeutic response in melanoma |
| title_full | Microsomal glutathione transferase 1 controls metastasis and therapeutic response in melanoma |
| title_fullStr | Microsomal glutathione transferase 1 controls metastasis and therapeutic response in melanoma |
| title_full_unstemmed | Microsomal glutathione transferase 1 controls metastasis and therapeutic response in melanoma |
| title_short | Microsomal glutathione transferase 1 controls metastasis and therapeutic response in melanoma |
| title_sort | microsomal glutathione transferase 1 controls metastasis and therapeutic response in melanoma |
| topic | Microsomal glutathione transferase 1 Melanoma Ferroptosis Oxidative stress Redox Metastasis |
| url | http://www.sciencedirect.com/science/article/pii/S1043661823002554 |
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