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Published on: June 9, 2023
Brucein D suppresses breast cancer proliferation and migration via targeting the FAK/LRG1 signaling pathway
Lin Li1, Haoyang Shen2, Yu Qiu2
1Department of Breast Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo, China. lhllilin@nbu.edu.cn.
Abstract:
Breast cancer (BC) is a leading cause of cancer-related mortality in women worldwide, underscoring the need for novel therapeutic strategies. Focal adhesion kinase (FAK) has emerged as a promising oncological target due to its central role in tumor progression. Bruceine D (BD), a natural compound from Brucea javanica, exhibits anti-cancer properties, but its mechanism in BC via FAK inhibition remains unclear. We conducted a comprehensive investigation using BC cell lines. Cell viability and migration were assessed by MTT and transwell assays, respectively. The tube formation assay examines the effect of BD on angiogenesis. Mitochondrial function was evaluated by measuring reactive oxygen species (ROS), ATP production, and mitochondrial membrane potential (ΔΨm). Apoptosis was quantified via flow cytometry. RNA sequencing (RNA-seq) with pathway enrichment analysis was employed to identify FAK-associated signaling pathways, and key protein expression changes, including FAK and downstream factors, were validated by western blotting. BD significantly suppressed BC cell proliferation, migration, and angiogenesis by inducing mitochondrial dysfunction, characterized by elevated ROS levels, depleted ATP, and loss of ΔΨm. Clinical analysis confirmed FAK overexpression in BC tissues. Mechanistically, BD inhibited FAK signaling. RNA-seq further revealed that FAK inhibition modulated several downstream pathways, including the expression of LRG1, collectively leading to the induction of apoptosis. This study identifies BD as a potent small-molecule FAK inhibitor. Our findings delineate a FAK-centered mechanism of action for BD, supporting its further development as a promising therapeutic agent for BC.
Insights
Bruceine D (BD) effectively inhibits breast cancer (BC) progression by targeting focal adhesion kinase (FAK). This natural compound induces mitochondrial dysfunction and apoptosis, offering a promising therapeutic avenue for BC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Breast cancer (BC) remains a significant global health challenge, necessitating innovative treatments.
- Focal adhesion kinase (FAK) plays a crucial role in tumor progression and is a key therapeutic target.
- Bruceine D (BD), a natural compound, shows anti-cancer potential, but its precise mechanism in BC, particularly regarding FAK inhibition, requires elucidation.
Purpose of the Study:
- To investigate the anti-cancer mechanism of Bruceine D (BD) in breast cancer (BC) through the lens of focal adhesion kinase (FAK) inhibition.
- To evaluate the effects of BD on BC cell proliferation, migration, angiogenesis, mitochondrial function, and apoptosis.
- To identify FAK-associated signaling pathways modulated by BD using RNA sequencing and validate key protein expression.
Main Methods:
- Utilized breast cancer cell lines for in vitro experiments.
- Assessed cell viability (MTT assay), migration (Transwell assay), and angiogenesis (tube formation assay).
- Evaluated mitochondrial function (ROS, ATP, ΔΨm), apoptosis (flow cytometry), and protein expression (Western blotting). Performed RNA sequencing for pathway analysis.
Main Results:
- BD significantly inhibited BC cell proliferation, migration, and angiogenesis.
- BD induced mitochondrial dysfunction, evidenced by increased ROS, decreased ATP, and loss of mitochondrial membrane potential.
- BD treatment led to apoptosis induction and was confirmed to inhibit FAK signaling, modulating downstream pathways including LRG1 expression.
Conclusions:
- Bruceine D (BD) demonstrates potent anti-cancer activity against breast cancer (BC) by inhibiting focal adhesion kinase (FAK) signaling.
- BD induces apoptosis and suppresses tumor progression via mitochondrial dysfunction.
- BD represents a promising small-molecule therapeutic candidate for BC, warranting further clinical development.
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