Inhibitory Impact Of Cinobufagin In Triple-Negative Breast Cancer Metastasis : Involvements Of Macrophage Reprogramming Through Upregulated MME and Inactivated FAK/STAT3 Signaling
Copyright © 2024 Elsevier Inc. All rights reserved..
BACKGROUND: Cinobufagin (CBG), a key bioactive component in cinobufacini, exhibits antitumor properties. This study explores CBG's impact on triple-negative breast cancer (TNBC) metastasis and elucidates the underpinning mechanism.
METHODS: Murine xenograft and orthotopic metastatic TNBC models were generated and treated with CBG. The burden of metastatic tumor in the mouse lung, the epithelial to mesenchymal transition (EMT) markers, and macrophage polarization markers within the tumors were examined. The phenotype of tumor-associated macrophages (TAMs) and mobility of TNBCs in vitro in a macrophage-TNBC cell coculture system were analyzed. Physiological targets of CBG were identified by bioinformatics analyses.
RESULTS: CBG treatment significantly alleviated lung tumor burden and EMT activity. It triggered an M2-to-M1 shift in TAMs, resulting in decreased TNBC cell migration, invasion, and EMT in vitro. CBG upregulated membrane metalloendopeptidase (MME) expression, suppressing FAK and STAT3 phosphorylation. Silencing of MME, either in mice or TAMs, counteracted CBG effects, reinstating M2 TAM predominance and enhancing TNBC cell metastasis. Cotreatment with Defactinib, a FAK antagonist, reversed M2 TAM polarization and TNBC cell metastasis. Notably, MME silencing in TNBC cells had no impact on CBG-suppressed malignant properties, indicating MME's indirect involvement in TNBC cell behavior through TAM mediation.
CONCLUSION: This study unveils CBG's ability to enhance MME expression, deactivate FAK/STAT3 signaling, and inhibit TNBC metastasis by suppressing M2-skewed macrophages.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
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| Enthalten in: |
Clinical breast cancer - (2024) vom: 26. Jan. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zhu, Zhaohui [VerfasserIn] |
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| Links: |
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| Themen: |
Bioinformatics |
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| Anmerkungen: |
Date Revised 20.02.2024 published: Print-Electronic Citation Status Publisher |
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| doi: |
10.1016/j.clbc.2024.01.014 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM368683842 |
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| 500 | |a published: Print-Electronic | ||
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| 520 | |a Copyright © 2024 Elsevier Inc. All rights reserved. | ||
| 520 | |a BACKGROUND: Cinobufagin (CBG), a key bioactive component in cinobufacini, exhibits antitumor properties. This study explores CBG's impact on triple-negative breast cancer (TNBC) metastasis and elucidates the underpinning mechanism | ||
| 520 | |a METHODS: Murine xenograft and orthotopic metastatic TNBC models were generated and treated with CBG. The burden of metastatic tumor in the mouse lung, the epithelial to mesenchymal transition (EMT) markers, and macrophage polarization markers within the tumors were examined. The phenotype of tumor-associated macrophages (TAMs) and mobility of TNBCs in vitro in a macrophage-TNBC cell coculture system were analyzed. Physiological targets of CBG were identified by bioinformatics analyses | ||
| 520 | |a RESULTS: CBG treatment significantly alleviated lung tumor burden and EMT activity. It triggered an M2-to-M1 shift in TAMs, resulting in decreased TNBC cell migration, invasion, and EMT in vitro. CBG upregulated membrane metalloendopeptidase (MME) expression, suppressing FAK and STAT3 phosphorylation. Silencing of MME, either in mice or TAMs, counteracted CBG effects, reinstating M2 TAM predominance and enhancing TNBC cell metastasis. Cotreatment with Defactinib, a FAK antagonist, reversed M2 TAM polarization and TNBC cell metastasis. Notably, MME silencing in TNBC cells had no impact on CBG-suppressed malignant properties, indicating MME's indirect involvement in TNBC cell behavior through TAM mediation | ||
| 520 | |a CONCLUSION: This study unveils CBG's ability to enhance MME expression, deactivate FAK/STAT3 signaling, and inhibit TNBC metastasis by suppressing M2-skewed macrophages | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Bioinformatics | |
| 650 | 4 | |a Defactinib | |
| 650 | 4 | |a Epithelial to mesenchymal transition | |
| 650 | 4 | |a Polarization | |
| 650 | 4 | |a Tumor-associated macrophages | |
| 700 | 1 | |a Wang, Hanlu |e verfasserin |4 aut | |
| 700 | 1 | |a Qian, Xu |e verfasserin |4 aut | |
| 700 | 1 | |a Xue, Meiling |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Aijun |e verfasserin |4 aut | |
| 700 | 1 | |a Yin, Yifei |e verfasserin |4 aut | |
| 700 | 1 | |a Tang, Jinhai |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Jian |e verfasserin |4 aut | |
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