Identification of INFG/STAT1/NOTCH3 as γ-Mangostin's potential targets for overcoming doxorubicin resistance and reducing cancer-associated fibroblasts in triple-negative breast cancer
Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved..
Triple-negative breast cancer (TNBC) is a very aggressive subtype of breast cancer characterized by drug resistance and distant metastasis. Cancer stem cells (CSCs) are considered a major contributor to TNBC's drug resistance. Thus targeting and eliminating CSCs have been vigorously researched. However, the precise targetable molecular networks responsible for CSC genesis remain unclear; this conundrum is mainly due to the high heterogeneity of the TNBC tumor microenvironment (TME). The cancer-associated fibroblasts (CAFs) are one of the most abundant cellular components of the TME. Emerging studies indicate that CAFs facilitate TNBC's progression by establishing a pro-tumor TME. Hence, identifying the molecular networks involved in CAF transformation and CAF-associated oncogenesis are essential areas to be explored. Through a bioinformatics approach, we identified INFG/STAT1/NOTCH3 as a molecular link between CSCs and CAF. DOX-resistant TNBC cell lines showed increased expression of INFG/STAT1/NOTCH3 and CD44 and were associated with increased self-renewal ability and CAF-transformative ability. Downregulation of STAT1 significantly reduced the tumorigenic properties of MDA-MB-231 and -468 cells and their CAF-transforming potential. Our molecular docking analysis suggested that gamma mangostin (gMG), a xanthone, formed complexes with INFG/STAT1/NOTCH3 better than celecoxib. We then demonstrated that gMG treatment reduced the tumorigenic properties similarly observed in STAT1-knocked down conditions. Finally, we utilized a DOX-resistant TNBC tumoroid-bearing mouse model to demonstrate that gMG treatment significantly delayed tumor growth, reduced CAF generation, and improved DOX sensitivity. Further investigations are warranted for clinical translation.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:163 |
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| Enthalten in: |
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie - 163(2023) vom: 01. Juli, Seite 114800 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Lawal, Bashir [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 29.05.2023 Date Revised 29.05.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.biopha.2023.114800 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved. | ||
| 520 | |a Triple-negative breast cancer (TNBC) is a very aggressive subtype of breast cancer characterized by drug resistance and distant metastasis. Cancer stem cells (CSCs) are considered a major contributor to TNBC's drug resistance. Thus targeting and eliminating CSCs have been vigorously researched. However, the precise targetable molecular networks responsible for CSC genesis remain unclear; this conundrum is mainly due to the high heterogeneity of the TNBC tumor microenvironment (TME). The cancer-associated fibroblasts (CAFs) are one of the most abundant cellular components of the TME. Emerging studies indicate that CAFs facilitate TNBC's progression by establishing a pro-tumor TME. Hence, identifying the molecular networks involved in CAF transformation and CAF-associated oncogenesis are essential areas to be explored. Through a bioinformatics approach, we identified INFG/STAT1/NOTCH3 as a molecular link between CSCs and CAF. DOX-resistant TNBC cell lines showed increased expression of INFG/STAT1/NOTCH3 and CD44 and were associated with increased self-renewal ability and CAF-transformative ability. Downregulation of STAT1 significantly reduced the tumorigenic properties of MDA-MB-231 and -468 cells and their CAF-transforming potential. Our molecular docking analysis suggested that gamma mangostin (gMG), a xanthone, formed complexes with INFG/STAT1/NOTCH3 better than celecoxib. We then demonstrated that gMG treatment reduced the tumorigenic properties similarly observed in STAT1-knocked down conditions. Finally, we utilized a DOX-resistant TNBC tumoroid-bearing mouse model to demonstrate that gMG treatment significantly delayed tumor growth, reduced CAF generation, and improved DOX sensitivity. Further investigations are warranted for clinical translation | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Cancer stem cells (CSCs) | |
| 650 | 4 | |a Cancer-associated fibroblasts (CAFs) | |
| 650 | 4 | |a Gamma mangostin (gMG) | |
| 650 | 4 | |a IFNG/STAT1/NOTCH signaling | |
| 650 | 4 | |a Triple-negative breast cancer (TNBC) | |
| 650 | 7 | |a mangostin |2 NLM | |
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| 650 | 7 | |a Doxorubicin |2 NLM | |
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| 650 | 7 | |a STAT1 protein, human |2 NLM | |
| 650 | 7 | |a STAT1 Transcription Factor |2 NLM | |
| 650 | 7 | |a NOTCH3 protein, human |2 NLM | |
| 650 | 7 | |a Receptor, Notch3 |2 NLM | |
| 650 | 7 | |a Stat1 protein, mouse |2 NLM | |
| 700 | 1 | |a Wu, Alexander Th |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Chien-Hsin |e verfasserin |4 aut | |
| 700 | 1 | |a T A, George |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Szu-Yuan |e verfasserin |4 aut | |
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