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

Biomedicine & Pharmacotherapy (Jul 2023)

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

Affiliations

Bashir Lawal: UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA; Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA
Alexander TH Wu: TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan; The Ph.D. Program of Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; Clinical Research Center, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan; Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 114, Taiwan
Chien-Hsin Chen: Department of Surgery, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; Department of Colorectal Surgery, Wan Fang Hospital, Taipei Medical University, Taipei 11031, Taiwan
George T.A: College of Medicine and Allied Health Sciences, University of Sierra Leone, Sierra Leone
Szu-Yuan Wu: Department of Food Nutrition and Health Biotechnology, College of Medical and Health Science, Asia University, Taichung, Taiwan; Department of Healthcare Administration, College of Medical and Health Science, Asia University, Taichung, Taiwan; Graduate Institute of Business Administration, College of Management, Fu Jen Catholic University, Taipei, Taiwan; Artificial Intelligence Development Centre, Fu Jen Catholic University, Taipei, Taiwan; Centre for Regional Anaesthesia and Pain Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Big Data Centre, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan, Taiwan; Division of Radiation Oncology, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan, Taiwan; Corresponding author at: Department of Healthcare Administration, College of Medical and Health Science, Asia University, Taichung, Taiwan.

Journal volume & issue: Vol. 163
p. 114800

Abstract

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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.

Published in Biomedicine & Pharmacotherapy

ISSN: 0753-3322 (Print); 1950-6007 (Online)
Publisher: Elsevier
Country of publisher: France
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.journals.elsevier.com/biomedicine-and-pharmacotherapy

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