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Cells
Volume 11
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10.3390/cells11223580
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Article

Targeting Wnt/β-Catenin Signaling Exacerbates Ferroptosis and Increases the Efficacy of Melanoma Immunotherapy via the Regulation of MITF

by
Hao Wang
,
Hengxiang Zhang
,
Yuhan Chen
,
Huina Wang
,
Yangzi Tian
,
Xiuli Yi
,
Qiong Shi
,
Tao Zhao
,
Baolu Zhang
,
Tianwen Gao
,
Sen Guo
,
Chunying Li
* and
Weinan Guo
*
Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
*
Authors to whom correspondence should be addressed.
Cells 2022, 11(22), 3580; https://doi.org/10.3390/cells11223580
Submission received: 18 October 2022 / Revised: 5 November 2022 / Accepted: 9 November 2022 / Published: 12 November 2022
(This article belongs to the Special Issue Novel Mechanisms and Therapeutic Opportunities of Ferroptosis)
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Abstract

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.
Keywords: Wnt/β-catenin; MITF; ferroptosis; melanoma; anti-PD-1 immunotherapy Wnt/β-catenin; MITF; ferroptosis; melanoma; anti-PD-1 immunotherapy

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MDPI and ACS Style

Wang, H.; Zhang, H.; Chen, Y.; Wang, H.; Tian, Y.; Yi, X.; Shi, Q.; Zhao, T.; Zhang, B.; Gao, T.; et al. Targeting Wnt/β-Catenin Signaling Exacerbates Ferroptosis and Increases the Efficacy of Melanoma Immunotherapy via the Regulation of MITF. Cells 2022, 11, 3580. https://doi.org/10.3390/cells11223580

AMA Style

Wang H, Zhang H, Chen Y, Wang H, Tian Y, Yi X, Shi Q, Zhao T, Zhang B, Gao T, et al. Targeting Wnt/β-Catenin Signaling Exacerbates Ferroptosis and Increases the Efficacy of Melanoma Immunotherapy via the Regulation of MITF. Cells. 2022; 11(22):3580. https://doi.org/10.3390/cells11223580

Chicago/Turabian Style

Wang, Hao, Hengxiang Zhang, Yuhan Chen, Huina Wang, Yangzi Tian, Xiuli Yi, Qiong Shi, Tao Zhao, Baolu Zhang, Tianwen Gao, and et al. 2022. "Targeting Wnt/β-Catenin Signaling Exacerbates Ferroptosis and Increases the Efficacy of Melanoma Immunotherapy via the Regulation of MITF" Cells 11, no. 22: 3580. https://doi.org/10.3390/cells11223580

APA Style

Wang, H., Zhang, H., Chen, Y., Wang, H., Tian, Y., Yi, X., Shi, Q., Zhao, T., Zhang, B., Gao, T., Guo, S., Li, C., & Guo, W. (2022). Targeting Wnt/β-Catenin Signaling Exacerbates Ferroptosis and Increases the Efficacy of Melanoma Immunotherapy via the Regulation of MITF. Cells, 11(22), 3580. https://doi.org/10.3390/cells11223580

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