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

Bashir Lawal, Alexander TH Wu, Chien Hsin Chen, George T.A, Szu Yuan Wu

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number114800
JournalBiomedicine and Pharmacotherapy
Volume163
DOIs
Publication statusPublished - Jul 2023

Keywords

  • Cancer stem cells (CSCs)
  • Cancer-associated fibroblasts (CAFs)
  • Gamma mangostin (gMG)
  • IFNG/STAT1/NOTCH signaling
  • Triple-negative breast cancer (TNBC)

ASJC Scopus subject areas

  • Pharmacology

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