Fisetin Inhibited Growth and Metastasis of Triple-Negative Breast Cancer by Reversing Epithelial-to-Mesenchymal Transition via PTEN/Akt/GSK3β Signal Pathway
Triple negative breast cancer (TNBC), characterized by its highly aggressive and metastatic features, is associated with poor prognosis and high mortality partly due to lack of effective treatment. Fisetin, a natural flavonoid compound, has been demonstrated to possess anti-cancer effects in various...
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doaj-726ad59b3b3f4d35b61ad3bcd23056262020-11-24T21:15:19ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122018-07-01910.3389/fphar.2018.00772381411Fisetin Inhibited Growth and Metastasis of Triple-Negative Breast Cancer by Reversing Epithelial-to-Mesenchymal Transition via PTEN/Akt/GSK3β Signal PathwayJie Li0Jie Li1Jie Li2Xia Gong3Rong Jiang4Dan Lin5Tao Zhou6Aijie Zhang7Hongzhong Li8Xiang Zhang9Jingyuan Wan10Ge Kuang11Hongyuan Li12Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, ChinaMolecular Oncology and Epigenetics Laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing, ChinaChongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, ChinaDepartment of Anatomy, Chongqing Medical University, Chongqing, ChinaLaboratory of Stem Cell and Tissue Engineering, Chongqing Medical University, Chongqing, ChinaChongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, ChinaChongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, ChinaDepartment of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, ChinaMolecular Oncology and Epigenetics Laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing, ChinaDepartment of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, ChinaChongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, ChinaChongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, ChinaDepartment of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, ChinaTriple negative breast cancer (TNBC), characterized by its highly aggressive and metastatic features, is associated with poor prognosis and high mortality partly due to lack of effective treatment. Fisetin, a natural flavonoid compound, has been demonstrated to possess anti-cancer effects in various cancers. However, the effects and mechanisms of fisetin on metastasis of TNBC remain uncovered. In this study, we found that fisetin dose-dependently inhibited cell proliferation, migration and invasion in TNBC cell lines MDA-MB-231 and BT549 cells. In addition, fisetin reversed epithelial to mesenchymal transition (EMT) as evaluated by cell morphology and EMT markers in MDA-MB-231 and BT549 cells. Furthermore, fisetin suppressed phosphoinositol 3-kinase (PI3K)-Akt-GSK-3β signaling pathway but upregulated the expression of PTEN mRNA and protein in a concentration-dependent manner. Further, silence of PTEN by siRNA abolished these benefits of fisetin on proliferation and metastasis of TNBCs. In vivo, using the metastatic breast cancer xenograft model bearing MDA-MB-231 cells, we found that fisetin dramatically inhibited growth of primary breast tumor and reduced lung metastasis, meanwhile, the expression of EMT molecules and PTEN/Akt/GSK-3β in primary and metastatic tissues changed in the same way as those in vitro experiments. In conclusion, all these results indicated that fisetin could effectively suppress proliferation and metastasis of TNBC and reverse EMT process, which might be mediated by PTEN/Akt/GSK-3β signaling pathway.https://www.frontiersin.org/article/10.3389/fphar.2018.00772/fullfisetintriple negative breast cancerEMTPTENAKT |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jie Li Jie Li Jie Li Xia Gong Rong Jiang Dan Lin Tao Zhou Aijie Zhang Hongzhong Li Xiang Zhang Jingyuan Wan Ge Kuang Hongyuan Li |
spellingShingle |
Jie Li Jie Li Jie Li Xia Gong Rong Jiang Dan Lin Tao Zhou Aijie Zhang Hongzhong Li Xiang Zhang Jingyuan Wan Ge Kuang Hongyuan Li Fisetin Inhibited Growth and Metastasis of Triple-Negative Breast Cancer by Reversing Epithelial-to-Mesenchymal Transition via PTEN/Akt/GSK3β Signal Pathway Frontiers in Pharmacology fisetin triple negative breast cancer EMT PTEN AKT |
author_facet |
Jie Li Jie Li Jie Li Xia Gong Rong Jiang Dan Lin Tao Zhou Aijie Zhang Hongzhong Li Xiang Zhang Jingyuan Wan Ge Kuang Hongyuan Li |
author_sort |
Jie Li |
title |
Fisetin Inhibited Growth and Metastasis of Triple-Negative Breast Cancer by Reversing Epithelial-to-Mesenchymal Transition via PTEN/Akt/GSK3β Signal Pathway |
title_short |
Fisetin Inhibited Growth and Metastasis of Triple-Negative Breast Cancer by Reversing Epithelial-to-Mesenchymal Transition via PTEN/Akt/GSK3β Signal Pathway |
title_full |
Fisetin Inhibited Growth and Metastasis of Triple-Negative Breast Cancer by Reversing Epithelial-to-Mesenchymal Transition via PTEN/Akt/GSK3β Signal Pathway |
title_fullStr |
Fisetin Inhibited Growth and Metastasis of Triple-Negative Breast Cancer by Reversing Epithelial-to-Mesenchymal Transition via PTEN/Akt/GSK3β Signal Pathway |
title_full_unstemmed |
Fisetin Inhibited Growth and Metastasis of Triple-Negative Breast Cancer by Reversing Epithelial-to-Mesenchymal Transition via PTEN/Akt/GSK3β Signal Pathway |
title_sort |
fisetin inhibited growth and metastasis of triple-negative breast cancer by reversing epithelial-to-mesenchymal transition via pten/akt/gsk3β signal pathway |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Pharmacology |
issn |
1663-9812 |
publishDate |
2018-07-01 |
description |
Triple negative breast cancer (TNBC), characterized by its highly aggressive and metastatic features, is associated with poor prognosis and high mortality partly due to lack of effective treatment. Fisetin, a natural flavonoid compound, has been demonstrated to possess anti-cancer effects in various cancers. However, the effects and mechanisms of fisetin on metastasis of TNBC remain uncovered. In this study, we found that fisetin dose-dependently inhibited cell proliferation, migration and invasion in TNBC cell lines MDA-MB-231 and BT549 cells. In addition, fisetin reversed epithelial to mesenchymal transition (EMT) as evaluated by cell morphology and EMT markers in MDA-MB-231 and BT549 cells. Furthermore, fisetin suppressed phosphoinositol 3-kinase (PI3K)-Akt-GSK-3β signaling pathway but upregulated the expression of PTEN mRNA and protein in a concentration-dependent manner. Further, silence of PTEN by siRNA abolished these benefits of fisetin on proliferation and metastasis of TNBCs. In vivo, using the metastatic breast cancer xenograft model bearing MDA-MB-231 cells, we found that fisetin dramatically inhibited growth of primary breast tumor and reduced lung metastasis, meanwhile, the expression of EMT molecules and PTEN/Akt/GSK-3β in primary and metastatic tissues changed in the same way as those in vitro experiments. In conclusion, all these results indicated that fisetin could effectively suppress proliferation and metastasis of TNBC and reverse EMT process, which might be mediated by PTEN/Akt/GSK-3β signaling pathway. |
topic |
fisetin triple negative breast cancer EMT PTEN AKT |
url |
https://www.frontiersin.org/article/10.3389/fphar.2018.00772/full |
work_keys_str_mv |
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