β-catenin-IRP2-primed iron availability to mitochondrial metabolism is druggable for active β-catenin-mediated cancer
Abstract Background Although β-catenin signaling cascade is frequently altered in human cancers, targeting this pathway has not been approved for cancer treatment. Methods High-throughput screening of an FDA-approved drug library was conducted to identify therapeutics that selectively inhibited the...
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| Format: | Article |
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BMC
2023-01-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-023-03914-0 |
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| author | Yuting Wu Shuhui Yang Luyang Han Kezhuo Shang Baohui Zhang Xiaochen Gai Weiwei Deng Fangming Liu Hongbing Zhang |
| author_facet | Yuting Wu Shuhui Yang Luyang Han Kezhuo Shang Baohui Zhang Xiaochen Gai Weiwei Deng Fangming Liu Hongbing Zhang |
| author_sort | Yuting Wu |
| collection | DOAJ |
| description | Abstract Background Although β-catenin signaling cascade is frequently altered in human cancers, targeting this pathway has not been approved for cancer treatment. Methods High-throughput screening of an FDA-approved drug library was conducted to identify therapeutics that selectively inhibited the cells with activated β-catenin. Efficacy of iron chelator and mitochondrial inhibitor was evaluated for suppression of cell proliferation and tumorigenesis. Cellular chelatable iron levels were measured to gain insight into the potential vulnerability of β-catenin-activated cells to iron deprivation. Extracellular flux analysis of mitochondrial function was conducted to evaluate the downstream events of iron deprivation. Chromatin immunoprecipitation, real-time quantitative PCR and immunoblotting were performed to identify β-catenin targets. Depletion of iron-regulatory protein 2 (IRP2), a key regulator of cellular iron homeostasis, was carried out to elucidate its significance in β-catenin-activated cells. Online databases were analyzed for correlation between β-catenin activity and IRP2-TfR1 axis in human cancers. Results Iron chelators were identified as selective inhibitors against β-catenin-activated cells. Deferoxamine mesylate, an iron chelator, preferentially repressed β-catenin-activated cell proliferation and tumor formation in mice. Mechanically, β-catenin stimulated the transcription of IRP2 to increase labile iron level. Depletion of IRP2-sequered iron impaired β-catenin-invigorated mitochondrial function. Moreover, mitochondrial inhibitor S-Gboxin selectively reduced β-catenin-associated cell viability and tumor formation. Conclusions β-catenin/IRP2/iron stimulation of mitochondrial energetics is targetable vulnerability of β-catenin-potentiated cancer. |
| first_indexed | 2024-04-10T19:41:02Z |
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| id | doaj.art-80960a3608ac4b7ca6ff9a379051749b |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-04-10T19:41:02Z |
| publishDate | 2023-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-80960a3608ac4b7ca6ff9a379051749b2023-01-29T12:20:40ZengBMCJournal of Translational Medicine1479-58762023-01-0121111410.1186/s12967-023-03914-0β-catenin-IRP2-primed iron availability to mitochondrial metabolism is druggable for active β-catenin-mediated cancerYuting Wu0Shuhui Yang1Luyang Han2Kezhuo Shang3Baohui Zhang4Xiaochen Gai5Weiwei Deng6Fangming Liu7Hongbing Zhang8State Key Laboratory of Medical Molecular Biology, Haihe Laboratory of Cell Ecosystem, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical CollegeState Key Laboratory of Medical Molecular Biology, Haihe Laboratory of Cell Ecosystem, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical CollegeState Key Laboratory of Medical Molecular Biology, Haihe Laboratory of Cell Ecosystem, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical CollegeState Key Laboratory of Medical Molecular Biology, Haihe Laboratory of Cell Ecosystem, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical CollegeDepartment of Physiology, School of Life Science, China Medical UniversityState Key Laboratory of Medical Molecular Biology, Haihe Laboratory of Cell Ecosystem, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical CollegeState Key Laboratory of Medical Molecular Biology, Haihe Laboratory of Cell Ecosystem, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical CollegeState Key Laboratory of Medical Molecular Biology, Haihe Laboratory of Cell Ecosystem, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical CollegeState Key Laboratory of Medical Molecular Biology, Haihe Laboratory of Cell Ecosystem, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical CollegeAbstract Background Although β-catenin signaling cascade is frequently altered in human cancers, targeting this pathway has not been approved for cancer treatment. Methods High-throughput screening of an FDA-approved drug library was conducted to identify therapeutics that selectively inhibited the cells with activated β-catenin. Efficacy of iron chelator and mitochondrial inhibitor was evaluated for suppression of cell proliferation and tumorigenesis. Cellular chelatable iron levels were measured to gain insight into the potential vulnerability of β-catenin-activated cells to iron deprivation. Extracellular flux analysis of mitochondrial function was conducted to evaluate the downstream events of iron deprivation. Chromatin immunoprecipitation, real-time quantitative PCR and immunoblotting were performed to identify β-catenin targets. Depletion of iron-regulatory protein 2 (IRP2), a key regulator of cellular iron homeostasis, was carried out to elucidate its significance in β-catenin-activated cells. Online databases were analyzed for correlation between β-catenin activity and IRP2-TfR1 axis in human cancers. Results Iron chelators were identified as selective inhibitors against β-catenin-activated cells. Deferoxamine mesylate, an iron chelator, preferentially repressed β-catenin-activated cell proliferation and tumor formation in mice. Mechanically, β-catenin stimulated the transcription of IRP2 to increase labile iron level. Depletion of IRP2-sequered iron impaired β-catenin-invigorated mitochondrial function. Moreover, mitochondrial inhibitor S-Gboxin selectively reduced β-catenin-associated cell viability and tumor formation. Conclusions β-catenin/IRP2/iron stimulation of mitochondrial energetics is targetable vulnerability of β-catenin-potentiated cancer.https://doi.org/10.1186/s12967-023-03914-0β-cateninIRP2Labile iron poolIron chelatorMitochondrial function |
| spellingShingle | Yuting Wu Shuhui Yang Luyang Han Kezhuo Shang Baohui Zhang Xiaochen Gai Weiwei Deng Fangming Liu Hongbing Zhang β-catenin-IRP2-primed iron availability to mitochondrial metabolism is druggable for active β-catenin-mediated cancer Journal of Translational Medicine β-catenin IRP2 Labile iron pool Iron chelator Mitochondrial function |
| title | β-catenin-IRP2-primed iron availability to mitochondrial metabolism is druggable for active β-catenin-mediated cancer |
| title_full | β-catenin-IRP2-primed iron availability to mitochondrial metabolism is druggable for active β-catenin-mediated cancer |
| title_fullStr | β-catenin-IRP2-primed iron availability to mitochondrial metabolism is druggable for active β-catenin-mediated cancer |
| title_full_unstemmed | β-catenin-IRP2-primed iron availability to mitochondrial metabolism is druggable for active β-catenin-mediated cancer |
| title_short | β-catenin-IRP2-primed iron availability to mitochondrial metabolism is druggable for active β-catenin-mediated cancer |
| title_sort | β catenin irp2 primed iron availability to mitochondrial metabolism is druggable for active β catenin mediated cancer |
| topic | β-catenin IRP2 Labile iron pool Iron chelator Mitochondrial function |
| url | https://doi.org/10.1186/s12967-023-03914-0 |
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