Anti-TNBC effects of Lappaol F by targeting epithelial-mesenchymal transition via regulation of GSK-3β/YAP/β-catenin and PI3K/AKT pathways
PurposeLappaol F (LAF), a lignan extracted from Fructus Arctii, has a wide spectrum of anti-tumor effects, including inhibition of TNBC cell growth. However, the pharmacological mechanism of LAF targeting epithelial-mesenchymal transition (EMT) to inhibit Triple-negative breast cancer (TNBC) growth...
Saved in:
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2025-02-01
|
| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2025.1496511/full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1825206707707445248 |
|---|---|
| author | Qiqi Meng Qiqi Meng Zhiping Li Xiaofeng He Yuanhao Hu Guiyun Wu Jiawen Huang Zhuohui Luo Zhuohui Luo Yingjie Hu Xiaoling Shen |
| author_facet | Qiqi Meng Qiqi Meng Zhiping Li Xiaofeng He Yuanhao Hu Guiyun Wu Jiawen Huang Zhuohui Luo Zhuohui Luo Yingjie Hu Xiaoling Shen |
| author_sort | Qiqi Meng |
| collection | DOAJ |
| description | PurposeLappaol F (LAF), a lignan extracted from Fructus Arctii, has a wide spectrum of anti-tumor effects, including inhibition of TNBC cell growth. However, the pharmacological mechanism of LAF targeting epithelial-mesenchymal transition (EMT) to inhibit Triple-negative breast cancer (TNBC) growth remains poorly understood. The present study aimed to reveal the potential mechanism of LAF against TNBC by in vivo and in vitro experiments.MethodsIn situ, transplantation-induced MDA-MB-231 solid tumor model in NCG mice and cultured MDA-MB-231 and Hs-578T cells were used to evaluate the anti-TNBC effect of LAF. Flow cytometry, wound healing, transwell assay, western blot, RT-PCR, and immunofluorescence analysis were carried out to investigate the pharmacological mechanism of LAF against TNBC.ResultsLAF significantly inhibited the growth of MDA-MB-231 tumors, with downregulated tumor level of vimentin and upregulated level of ZO-1. In MDA-MB-231 and Hs-578T cells, LAF markedly suppressed cell proliferation, migration and invasion, and promoted apoptosis. Similarly, LAF increased the expression of ZO-1 and occludin proteins in MDA-MB-231 cells, and inhibited the expression of vimentin, snail and slug proteins in MDA-MB-231 and Hs-578T cells, as well as the expression of N-caderin in Hs-578T cells. Moreover, LAF also inhibited the phosphorylation of GSK-3β, thereby inhibited the downstream nuclear translocation of β-catenin and the expression of YAP. Furthermore, LAF significantly inhibited the expression of PI3K and AKT, and the phosphorylation of downstream mTOR.ConclusionLAF showed anti-TNBC effect both in vitro and in vivo. Reversal of EMT by inhibiting GSK-3β/YAP/β-catenin signaling and PI3K/AKT/mTOR signaling contributes to the effect. |
| format | Article |
| id | doaj-art-42a46520ce7847eaa665f9bdccca8d9a |
| institution | Kabale University |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj-art-42a46520ce7847eaa665f9bdccca8d9a2025-02-07T06:49:31ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-02-011610.3389/fphar.2025.14965111496511Anti-TNBC effects of Lappaol F by targeting epithelial-mesenchymal transition via regulation of GSK-3β/YAP/β-catenin and PI3K/AKT pathwaysQiqi Meng0Qiqi Meng1Zhiping Li2Xiaofeng He3Yuanhao Hu4Guiyun Wu5Jiawen Huang6Zhuohui Luo7Zhuohui Luo8Yingjie Hu9Xiaoling Shen10Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, ChinaInternational Institute for Translational Chinese Medicine, School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, ChinaScience and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, ChinaScience and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, ChinaScience and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, ChinaScience and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, ChinaScience and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, ChinaResearch Center for Drug Safety Evaluation of Hainan Province, Hainan Medical University, Haikou, Hainan, ChinaHainan Pharmaceutical Research and Development Science Park, Haikou, Hainan, ChinaScience and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, ChinaScience and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, ChinaPurposeLappaol F (LAF), a lignan extracted from Fructus Arctii, has a wide spectrum of anti-tumor effects, including inhibition of TNBC cell growth. However, the pharmacological mechanism of LAF targeting epithelial-mesenchymal transition (EMT) to inhibit Triple-negative breast cancer (TNBC) growth remains poorly understood. The present study aimed to reveal the potential mechanism of LAF against TNBC by in vivo and in vitro experiments.MethodsIn situ, transplantation-induced MDA-MB-231 solid tumor model in NCG mice and cultured MDA-MB-231 and Hs-578T cells were used to evaluate the anti-TNBC effect of LAF. Flow cytometry, wound healing, transwell assay, western blot, RT-PCR, and immunofluorescence analysis were carried out to investigate the pharmacological mechanism of LAF against TNBC.ResultsLAF significantly inhibited the growth of MDA-MB-231 tumors, with downregulated tumor level of vimentin and upregulated level of ZO-1. In MDA-MB-231 and Hs-578T cells, LAF markedly suppressed cell proliferation, migration and invasion, and promoted apoptosis. Similarly, LAF increased the expression of ZO-1 and occludin proteins in MDA-MB-231 cells, and inhibited the expression of vimentin, snail and slug proteins in MDA-MB-231 and Hs-578T cells, as well as the expression of N-caderin in Hs-578T cells. Moreover, LAF also inhibited the phosphorylation of GSK-3β, thereby inhibited the downstream nuclear translocation of β-catenin and the expression of YAP. Furthermore, LAF significantly inhibited the expression of PI3K and AKT, and the phosphorylation of downstream mTOR.ConclusionLAF showed anti-TNBC effect both in vitro and in vivo. Reversal of EMT by inhibiting GSK-3β/YAP/β-catenin signaling and PI3K/AKT/mTOR signaling contributes to the effect.https://www.frontiersin.org/articles/10.3389/fphar.2025.1496511/fullArctium lappa LLappaol Ftriple negative breast cancerepithelial-mesenchymal transitionGSK-3β/YAP/β-catenin signalingPI3K/AKT signaling |
| spellingShingle | Qiqi Meng Qiqi Meng Zhiping Li Xiaofeng He Yuanhao Hu Guiyun Wu Jiawen Huang Zhuohui Luo Zhuohui Luo Yingjie Hu Xiaoling Shen Anti-TNBC effects of Lappaol F by targeting epithelial-mesenchymal transition via regulation of GSK-3β/YAP/β-catenin and PI3K/AKT pathways Frontiers in Pharmacology Arctium lappa L Lappaol F triple negative breast cancer epithelial-mesenchymal transition GSK-3β/YAP/β-catenin signaling PI3K/AKT signaling |
| title | Anti-TNBC effects of Lappaol F by targeting epithelial-mesenchymal transition via regulation of GSK-3β/YAP/β-catenin and PI3K/AKT pathways |
| title_full | Anti-TNBC effects of Lappaol F by targeting epithelial-mesenchymal transition via regulation of GSK-3β/YAP/β-catenin and PI3K/AKT pathways |
| title_fullStr | Anti-TNBC effects of Lappaol F by targeting epithelial-mesenchymal transition via regulation of GSK-3β/YAP/β-catenin and PI3K/AKT pathways |
| title_full_unstemmed | Anti-TNBC effects of Lappaol F by targeting epithelial-mesenchymal transition via regulation of GSK-3β/YAP/β-catenin and PI3K/AKT pathways |
| title_short | Anti-TNBC effects of Lappaol F by targeting epithelial-mesenchymal transition via regulation of GSK-3β/YAP/β-catenin and PI3K/AKT pathways |
| title_sort | anti tnbc effects of lappaol f by targeting epithelial mesenchymal transition via regulation of gsk 3β yap β catenin and pi3k akt pathways |
| topic | Arctium lappa L Lappaol F triple negative breast cancer epithelial-mesenchymal transition GSK-3β/YAP/β-catenin signaling PI3K/AKT signaling |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2025.1496511/full |
| work_keys_str_mv | AT qiqimeng antitnbceffectsoflappaolfbytargetingepithelialmesenchymaltransitionviaregulationofgsk3byapbcateninandpi3kaktpathways AT qiqimeng antitnbceffectsoflappaolfbytargetingepithelialmesenchymaltransitionviaregulationofgsk3byapbcateninandpi3kaktpathways AT zhipingli antitnbceffectsoflappaolfbytargetingepithelialmesenchymaltransitionviaregulationofgsk3byapbcateninandpi3kaktpathways AT xiaofenghe antitnbceffectsoflappaolfbytargetingepithelialmesenchymaltransitionviaregulationofgsk3byapbcateninandpi3kaktpathways AT yuanhaohu antitnbceffectsoflappaolfbytargetingepithelialmesenchymaltransitionviaregulationofgsk3byapbcateninandpi3kaktpathways AT guiyunwu antitnbceffectsoflappaolfbytargetingepithelialmesenchymaltransitionviaregulationofgsk3byapbcateninandpi3kaktpathways AT jiawenhuang antitnbceffectsoflappaolfbytargetingepithelialmesenchymaltransitionviaregulationofgsk3byapbcateninandpi3kaktpathways AT zhuohuiluo antitnbceffectsoflappaolfbytargetingepithelialmesenchymaltransitionviaregulationofgsk3byapbcateninandpi3kaktpathways AT zhuohuiluo antitnbceffectsoflappaolfbytargetingepithelialmesenchymaltransitionviaregulationofgsk3byapbcateninandpi3kaktpathways AT yingjiehu antitnbceffectsoflappaolfbytargetingepithelialmesenchymaltransitionviaregulationofgsk3byapbcateninandpi3kaktpathways AT xiaolingshen antitnbceffectsoflappaolfbytargetingepithelialmesenchymaltransitionviaregulationofgsk3byapbcateninandpi3kaktpathways |