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Chrysophanol attenuates breast cancer angiogenesis through blocking VEGFA/VEGFR2/ERK activation via inhibiting ACE2
Tong Zhao1, Luying Xu2, Wenjie Huang2
1Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China; School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
Background:
Breast cancer progression depends on abnormal angiogenesis, driven by VEGF/VEGFR2/ERK and inhibited by Angiotensin-Converting Enzyme 2 (ACE2). Chrysophanol (CHR) shows anti-breast cancer efficacy, but its mechanism is unclear.
Methods:
Anti-tumor effects were assessed by measuring tumor volume, H&E staining, Ki67 immunohistochemistry, MTT, scratch wound, and Transwell assays. Anti-angiogenic effects were evaluated via Platelet Endothelial Cell Adhesion Molecule-1 (CD31) immunohistochemistry, CAM assay and Western blot (WB) of VEGF-A, Hypoxia-Inducible Factor 1-α (HIF-1α), and VEGFA/VEGFR2/ERK pathway proteins. The mechanism was explored by WB analysis of ACE2 expression/ubiquitination, validated by siRNA knockdown and CETSA for binding site identification.
Results:
Both in vivo and in vitro experiments demonstrated that chrysophanol reduces tumor cell viability, suppresses tumor cell growth, migration, and invasion, inhibiting the progression of breast cancer. Given the critical role of angiogenesis in tumor development, further studies revealed that chrysophanol downregulates the expression of proteins such as HIF-1α and Vascular Endothelial Growth Factor A (VEGFA), indicating that it inhibits tumor angiogenesis by suppressing the VEGFA/VEGFR2/ERK signaling pathway. Since prior evidence suggests that this pathway acts downstream of ACE2, we examined ACE2 protein levels and found that chrysophanol reduces ACE2 ubiquitination, and enhances its stability and expression. This upregulation of ACE2 further inhibits the downstream VEGFA/VEGFR2/ERK pathway. Moreover, molecular docking confirmed that chrysophanol binds specifically to the active pocket 888 of the ACE2 protein. All the observed inhibitory effects on breast cancer were dose-dependent.
Conclusion:
All the data shows that chrysophanol can reduce tumor angiogenesis and alleviate breast cancer growth. It also confirms that chrysophanol can promote ACE2 expression to inhibit the VEGFa/VEGFR2/ERK signaling pathway, thereby suppressing breast cancer development.
Insights
Chrysophanol inhibits breast cancer growth by reducing angiogenesis and promoting Angiotensin-Converting Enzyme 2 (ACE2) expression. This mechanism suppresses the VEGFa/VEGFR2/ERK pathway, offering a new therapeutic strategy for breast cancer.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Breast cancer progression is linked to abnormal angiogenesis, a process influenced by the VEGF/VEGFR2/ERK pathway and Angiotensin-Converting Enzyme 2 (ACE2).
- Chrysophanol (CHR) exhibits anti-breast cancer properties, but its underlying mechanism requires elucidation.
Purpose of the Study:
- To investigate the anti-tumor and anti-angiogenic mechanisms of Chrysophanol in breast cancer.
- To determine Chrysophanol's effect on the ACE2/VEGFa/VEGFR2/ERK signaling pathway.
Main Methods:
- In vivo and in vitro assays including tumor volume measurement, H&E staining, Ki67 IHC, MTT, scratch wound, and Transwell assays.
- Assessment of anti-angiogenic effects via CD31 IHC, CAM assay, and Western blot for key pathway proteins.
- Exploration of mechanism through Western blot for ACE2 expression/ubiquitination, siRNA knockdown, and CETSA.
Main Results:
- Chrysophanol significantly reduced breast cancer cell viability, growth, migration, and invasion in vitro and in vivo.
- Chrysophanol inhibited tumor angiogenesis by downregulating HIF-1α and VEGFA, suppressing the VEGFA/VEGFR2/ERK pathway.
- Chrysophanol enhanced ACE2 stability and expression by reducing its ubiquitination, which further inhibited the VEGFA/VEGFR2/ERK pathway. Molecular docking confirmed Chrysophanol binding to ACE2.
Conclusions:
- Chrysophanol effectively inhibits breast cancer growth and angiogenesis.
- Chrysophanol promotes ACE2 expression, which in turn inhibits the VEGFA/VEGFR2/ERK pathway, thereby suppressing breast cancer development.
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