Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Wang, Hao, Zhang, Hengxiang, Chen, Yuhan, Wang, Huina, Tian, Yangzi, Yi, Xiuli, Shi, Qiong, Zhao, Tao, Zhang, Baolu, Gao, Tianwen, Guo, Sen, Li, Chunying, Guo, Weinan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9688625/
https://www.ncbi.nlm.nih.gov/pubmed/36429010
http://dx.doi.org/10.3390/cells11223580
_version_ 1784836316712665088
author Wang, Hao
Zhang, Hengxiang
Chen, Yuhan
Wang, Huina
Tian, Yangzi
Yi, Xiuli
Shi, Qiong
Zhao, Tao
Zhang, Baolu
Gao, Tianwen
Guo, Sen
Li, Chunying
Guo, Weinan
author_facet Wang, Hao
Zhang, Hengxiang
Chen, Yuhan
Wang, Huina
Tian, Yangzi
Yi, Xiuli
Shi, Qiong
Zhao, Tao
Zhang, Baolu
Gao, Tianwen
Guo, Sen
Li, Chunying
Guo, Weinan
author_sort Wang, Hao
collection PubMed
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.
format Online
Article
Text
id pubmed-9688625
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-96886252022-11-25 Targeting Wnt/β-Catenin Signaling Exacerbates Ferroptosis and Increases the Efficacy of Melanoma Immunotherapy via the Regulation of MITF Wang, Hao Zhang, Hengxiang Chen, Yuhan Wang, Huina Tian, Yangzi Yi, Xiuli Shi, Qiong Zhao, Tao Zhang, Baolu Gao, Tianwen Guo, Sen Li, Chunying Guo, Weinan Cells Article 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. MDPI 2022-11-12 /pmc/articles/PMC9688625/ /pubmed/36429010 http://dx.doi.org/10.3390/cells11223580 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wang, Hao
Zhang, Hengxiang
Chen, Yuhan
Wang, Huina
Tian, Yangzi
Yi, Xiuli
Shi, Qiong
Zhao, Tao
Zhang, Baolu
Gao, Tianwen
Guo, Sen
Li, Chunying
Guo, Weinan
Targeting Wnt/β-Catenin Signaling Exacerbates Ferroptosis and Increases the Efficacy of Melanoma Immunotherapy via the Regulation of MITF
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 Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9688625/
https://www.ncbi.nlm.nih.gov/pubmed/36429010
http://dx.doi.org/10.3390/cells11223580
work_keys_str_mv AT wanghao targetingwntbcateninsignalingexacerbatesferroptosisandincreasestheefficacyofmelanomaimmunotherapyviatheregulationofmitf
AT zhanghengxiang targetingwntbcateninsignalingexacerbatesferroptosisandincreasestheefficacyofmelanomaimmunotherapyviatheregulationofmitf
AT chenyuhan targetingwntbcateninsignalingexacerbatesferroptosisandincreasestheefficacyofmelanomaimmunotherapyviatheregulationofmitf
AT wanghuina targetingwntbcateninsignalingexacerbatesferroptosisandincreasestheefficacyofmelanomaimmunotherapyviatheregulationofmitf
AT tianyangzi targetingwntbcateninsignalingexacerbatesferroptosisandincreasestheefficacyofmelanomaimmunotherapyviatheregulationofmitf
AT yixiuli targetingwntbcateninsignalingexacerbatesferroptosisandincreasestheefficacyofmelanomaimmunotherapyviatheregulationofmitf
AT shiqiong targetingwntbcateninsignalingexacerbatesferroptosisandincreasestheefficacyofmelanomaimmunotherapyviatheregulationofmitf
AT zhaotao targetingwntbcateninsignalingexacerbatesferroptosisandincreasestheefficacyofmelanomaimmunotherapyviatheregulationofmitf
AT zhangbaolu targetingwntbcateninsignalingexacerbatesferroptosisandincreasestheefficacyofmelanomaimmunotherapyviatheregulationofmitf
AT gaotianwen targetingwntbcateninsignalingexacerbatesferroptosisandincreasestheefficacyofmelanomaimmunotherapyviatheregulationofmitf
AT guosen targetingwntbcateninsignalingexacerbatesferroptosisandincreasestheefficacyofmelanomaimmunotherapyviatheregulationofmitf
AT lichunying targetingwntbcateninsignalingexacerbatesferroptosisandincreasestheefficacyofmelanomaimmunotherapyviatheregulationofmitf
AT guoweinan targetingwntbcateninsignalingexacerbatesferroptosisandincreasestheefficacyofmelanomaimmunotherapyviatheregulationofmitf