Targeting Wnt/β-Catenin Signaling Exacerbates Ferroptosis and Increases the Efficacy of Melanoma Immunotherapy via the Regulation of MITF
Melanoma is the most lethal form of skin cancer, resulting from the malignant transformation of epidermal melanocytes. Recent revolutionary progress in targeted therapy and immunotherapy has prominently improved the treatment outcome, but the survival of melanoma patients remains suboptimal. Ferropt...
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2022-11-01
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| author | Hao Wang Hengxiang Zhang Yuhan Chen Huina Wang Yangzi Tian Xiuli Yi Qiong Shi Tao Zhao Baolu Zhang Tianwen Gao Sen Guo Chunying Li Weinan Guo |
| author_facet | Hao Wang Hengxiang Zhang Yuhan Chen Huina Wang Yangzi Tian Xiuli Yi Qiong Shi Tao Zhao Baolu Zhang Tianwen Gao Sen Guo Chunying Li Weinan Guo |
| author_sort | Hao Wang |
| collection | DOAJ |
| description | Melanoma is the most lethal form of skin cancer, resulting from the malignant transformation of epidermal melanocytes. Recent revolutionary progress in targeted therapy and immunotherapy has prominently improved the treatment outcome, but the survival of melanoma patients remains suboptimal. Ferroptosis is greatly involved in cancer pathogenesis and can execute the outcome of immunotherapy. However, the detailed regulatory mechanisms of melanoma cell ferroptosis remain elusive. Herein, we report that Wnt/β-catenin signaling regulates ferroptosis and melanoma immunotherapy efficacy via the regulation of MITF. First of all, we found that Wnt/β-catenin signaling was prominently suppressed in melanoma cell ferroptosis. Then, we proved that targeting β-catenin exacerbated melanoma cell ferroptosis by promoting the generation of lipid peroxidation both in vitro and in vivo. Subsequent mechanistic studies revealed that MITF mediated the effect of Wnt/β-catenin signaling on melanoma cell ferroptosis, and PGC1α and SCD1 were documented as two main effectors downstream of Wnt/β-catenin-MITF pathway. Ultimately, pharmacological inhibition of β-catenin or MITF increased the efficacy of anti-PD-1 immunotherapy in preclinical xenograft tumor model by promoting ferroptosis. Taken together, Wnt/β-catenin signaling deficiency exacerbates ferroptosis in melanoma via the regulation of MITF. Targeting Wnt/β-catenin-MITF pathway could be a promising strategy to potentiate ferroptosis and increase the efficacy of anti-PD-1 immunotherapy. |
| first_indexed | 2024-03-09T18:25:37Z |
| format | Article |
| id | doaj.art-ab145caa37604c80ad4ba7f7fd840534 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T18:25:37Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-ab145caa37604c80ad4ba7f7fd8405342023-11-24T07:57:44ZengMDPI AGCells2073-44092022-11-011122358010.3390/cells11223580Targeting Wnt/β-Catenin Signaling Exacerbates Ferroptosis and Increases the Efficacy of Melanoma Immunotherapy via the Regulation of MITFHao Wang0Hengxiang Zhang1Yuhan Chen2Huina Wang3Yangzi Tian4Xiuli Yi5Qiong Shi6Tao Zhao7Baolu Zhang8Tianwen Gao9Sen Guo10Chunying Li11Weinan Guo12Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, ChinaDepartment of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, ChinaDepartment of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, ChinaDepartment of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, ChinaDepartment of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, ChinaDepartment of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, ChinaDepartment of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, ChinaDepartment of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, ChinaDepartment of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, ChinaDepartment of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, ChinaDepartment of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, ChinaDepartment of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, ChinaDepartment of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, ChinaMelanoma is the most lethal form of skin cancer, resulting from the malignant transformation of epidermal melanocytes. Recent revolutionary progress in targeted therapy and immunotherapy has prominently improved the treatment outcome, but the survival of melanoma patients remains suboptimal. Ferroptosis is greatly involved in cancer pathogenesis and can execute the outcome of immunotherapy. However, the detailed regulatory mechanisms of melanoma cell ferroptosis remain elusive. Herein, we report that Wnt/β-catenin signaling regulates ferroptosis and melanoma immunotherapy efficacy via the regulation of MITF. First of all, we found that Wnt/β-catenin signaling was prominently suppressed in melanoma cell ferroptosis. Then, we proved that targeting β-catenin exacerbated melanoma cell ferroptosis by promoting the generation of lipid peroxidation both in vitro and in vivo. Subsequent mechanistic studies revealed that MITF mediated the effect of Wnt/β-catenin signaling on melanoma cell ferroptosis, and PGC1α and SCD1 were documented as two main effectors downstream of Wnt/β-catenin-MITF pathway. Ultimately, pharmacological inhibition of β-catenin or MITF increased the efficacy of anti-PD-1 immunotherapy in preclinical xenograft tumor model by promoting ferroptosis. Taken together, Wnt/β-catenin signaling deficiency exacerbates ferroptosis in melanoma via the regulation of MITF. Targeting Wnt/β-catenin-MITF pathway could be a promising strategy to potentiate ferroptosis and increase the efficacy of anti-PD-1 immunotherapy.https://www.mdpi.com/2073-4409/11/22/3580Wnt/β-cateninMITFferroptosismelanomaanti-PD-1 immunotherapy |
| spellingShingle | Hao Wang Hengxiang Zhang Yuhan Chen Huina Wang Yangzi Tian Xiuli Yi Qiong Shi Tao Zhao Baolu Zhang Tianwen Gao Sen Guo Chunying Li Weinan Guo Targeting Wnt/β-Catenin Signaling Exacerbates Ferroptosis and Increases the Efficacy of Melanoma Immunotherapy via the Regulation of MITF Cells Wnt/β-catenin MITF ferroptosis melanoma anti-PD-1 immunotherapy |
| title | Targeting Wnt/β-Catenin Signaling Exacerbates Ferroptosis and Increases the Efficacy of Melanoma Immunotherapy via the Regulation of MITF |
| title_full | Targeting Wnt/β-Catenin Signaling Exacerbates Ferroptosis and Increases the Efficacy of Melanoma Immunotherapy via the Regulation of MITF |
| title_fullStr | Targeting Wnt/β-Catenin Signaling Exacerbates Ferroptosis and Increases the Efficacy of Melanoma Immunotherapy via the Regulation of MITF |
| title_full_unstemmed | Targeting Wnt/β-Catenin Signaling Exacerbates Ferroptosis and Increases the Efficacy of Melanoma Immunotherapy via the Regulation of MITF |
| title_short | Targeting Wnt/β-Catenin Signaling Exacerbates Ferroptosis and Increases the Efficacy of Melanoma Immunotherapy via the Regulation of MITF |
| title_sort | targeting wnt β catenin signaling exacerbates ferroptosis and increases the efficacy of melanoma immunotherapy via the regulation of mitf |
| topic | Wnt/β-catenin MITF ferroptosis melanoma anti-PD-1 immunotherapy |
| url | https://www.mdpi.com/2073-4409/11/22/3580 |
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