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已发表论文
FAK 诱导的时间依赖性细胞反应谱分析：抗肿瘤免疫天然产物的预测、鉴定与分析
Authors Jin L, Chen M, Lou J, Fu J, Bai N, Liu X, Mao W, Li Z, Shou Q, Fu H
Received 29 May 2025
Accepted for publication 21 September 2025
Published 6 October 2025 Volume 2025:19 Pages 9079—9097
DOI https://doi.org/10.2147/DDDT.S533551
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 3
Editor who approved publication: Dr Solomon Tadesse Zeleke
Lu Jin,1,2,* Mengyun Chen,1,3,* Jingyi Lou,1,3,* Jianhui Fu,1,3 Ningning Bai,1 Xia Liu,1 Weiye Mao,1 Zhenghao Li,1,3 Qiyang Shou,1,3 Huiying Fu1– 3
1Second Clinical Medical School, Jinhua Academy, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China; 2College of Life Science, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 3School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Qiyang Shou, Second Clinical Medical School, Jinhua Academy, Zhejiang Chinese Medical University, No. 548 Binwen Road, Hangzhou, 310053, People’s Republic of China, Tel +86 571-8661-3662, Email sqy133@126.com Huiying Fu, Second Clinical Medical School, Jinhua Academy, Zhejiang Chinese Medical University, No. 548 Binwen Road, Hangzhou, 310053, People’s Republic of China, Tel +86 571-8661-3662, Email fhy131@126.com
Background: Focal Adhesion Kinase (FAK) is a key tyrosine kinase often overexpressed in tumors, making it a promising target for cancer therapy. This study aims to screen and investigate the activity and mechanisms of Traditional Chinese Medicines (TCMs) targeting FAK within breast cancer.
Materials and Methods: Using xCELLigence system, we identified TCMs affecting FAK signaling and validated its anti-tumor effects. The 4T1-Luc breast cancer models and MMTV-PyMT mice were used to evaluate Moutan Cortex Radicis (MCR) on tumor growth and lung metastasis, with flow cytometry assessing immune cell changes. We utilized CRISPR-Cas9 to investigate the anti-tumor mechanisms of MCR by specifically targeting the FAK signaling pathway. To elucidate the underlying molecular mechanisms, RNA sequencing was performed, and the results were subsequently validated through quantitative reverse transcription PCR (qRT-PCR) and Western blot analysis.
Results: We have successfully developed the EGF-induced Time-dependent Cell Response Profilings (FAK-TCRPs) and discovered that MCR effectively attenuated EGF-mediated responses in a dose-dependent manner. Additionally, MCR significantly inhibited tumor growth and lung metastasis by partly targeting FAK. MCR increased CD8+ T cell infiltration and the proportion of CD44HiCD62LHi central memory and CD44HiCD62LLow effector memory T cells, while reducing regulatory T cells (Tregs) and CTLA-4 expression. MCR converted M2 tumor-associated macrophages (TAMs) to M1 within the tumor microenvironment (TME). In FAK-deficient mice, MCR did not affect on CD8+ cells, TAMs, or CTLA-4 expression. MCR modulated chemokine signaling and ECM-receptor interactions, decreasing CCL1, CCL5, TGF, IL-4, IL-10, TNF-α, and IL-6, while increasing CCL7, CXCL10, and IL-24. It significantly inhibited FAK mRNA in tumors. Cellular experiments demonstrated that MCR suppressed P-FAK and P-Erk activation and reduced MMP-2, MMP-9, Laminin, and Fibronectin levels.
Conclusion: Collectively, MCR is identified as a FAK-targeting agent through FAK-TCRPs. MCR inhibits TAMs, CTLA-4, and chemokine transcription via the FAK/MMPs pathway, showing antitumor effects in breast cancer.
Keywords: FAK, time dependent cell response profilings, moutan cortex radicis, breast cancer, MMPs, immune cell
1Second Clinical Medical School, Jinhua Academy, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China; 2College of Life Science, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 3School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Qiyang Shou, Second Clinical Medical School, Jinhua Academy, Zhejiang Chinese Medical University, No. 548 Binwen Road, Hangzhou, 310053, People’s Republic of China, Tel +86 571-8661-3662, Email sqy133@126.com Huiying Fu, Second Clinical Medical School, Jinhua Academy, Zhejiang Chinese Medical University, No. 548 Binwen Road, Hangzhou, 310053, People’s Republic of China, Tel +86 571-8661-3662, Email fhy131@126.com
Background: Focal Adhesion Kinase (FAK) is a key tyrosine kinase often overexpressed in tumors, making it a promising target for cancer therapy. This study aims to screen and investigate the activity and mechanisms of Traditional Chinese Medicines (TCMs) targeting FAK within breast cancer.
Materials and Methods: Using xCELLigence system, we identified TCMs affecting FAK signaling and validated its anti-tumor effects. The 4T1-Luc breast cancer models and MMTV-PyMT mice were used to evaluate Moutan Cortex Radicis (MCR) on tumor growth and lung metastasis, with flow cytometry assessing immune cell changes. We utilized CRISPR-Cas9 to investigate the anti-tumor mechanisms of MCR by specifically targeting the FAK signaling pathway. To elucidate the underlying molecular mechanisms, RNA sequencing was performed, and the results were subsequently validated through quantitative reverse transcription PCR (qRT-PCR) and Western blot analysis.
Results: We have successfully developed the EGF-induced Time-dependent Cell Response Profilings (FAK-TCRPs) and discovered that MCR effectively attenuated EGF-mediated responses in a dose-dependent manner. Additionally, MCR significantly inhibited tumor growth and lung metastasis by partly targeting FAK. MCR increased CD8+ T cell infiltration and the proportion of CD44HiCD62LHi central memory and CD44HiCD62LLow effector memory T cells, while reducing regulatory T cells (Tregs) and CTLA-4 expression. MCR converted M2 tumor-associated macrophages (TAMs) to M1 within the tumor microenvironment (TME). In FAK-deficient mice, MCR did not affect on CD8+ cells, TAMs, or CTLA-4 expression. MCR modulated chemokine signaling and ECM-receptor interactions, decreasing CCL1, CCL5, TGF, IL-4, IL-10, TNF-α, and IL-6, while increasing CCL7, CXCL10, and IL-24. It significantly inhibited FAK mRNA in tumors. Cellular experiments demonstrated that MCR suppressed P-FAK and P-Erk activation and reduced MMP-2, MMP-9, Laminin, and Fibronectin levels.
Conclusion: Collectively, MCR is identified as a FAK-targeting agent through FAK-TCRPs. MCR inhibits TAMs, CTLA-4, and chemokine transcription via the FAK/MMPs pathway, showing antitumor effects in breast cancer.
Keywords: FAK, time dependent cell response profilings, moutan cortex radicis, breast cancer, MMPs, immune cell