Coptidis Rhizoma Suppresses Metastatic Behavior by Inhibiting TGF-β-Mediated Epithelial-Mesenchymal Transition in 5-FU-Resistant HCT116 Cells
Colorectal cancer (CRC) is the second most lethal malignancy worldwide. The high mortality rate of CRC is largely due to cancer metastasis. Recently, suppressing epithelial-to-mesenchymal transition (EMT) has been considered a promising strategy for treating metastatic cancer, especially drug-resist...
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Frontiers Media S.A.
2022-06-01
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author | Yong-Hwi Kang Jing-Hua Wang Jin-Seok Lee Nam-Hun Lee Nam-Hun Lee Chang-Gue Son |
author_facet | Yong-Hwi Kang Jing-Hua Wang Jin-Seok Lee Nam-Hun Lee Nam-Hun Lee Chang-Gue Son |
author_sort | Yong-Hwi Kang |
collection | DOAJ |
description | Colorectal cancer (CRC) is the second most lethal malignancy worldwide. The high mortality rate of CRC is largely due to cancer metastasis. Recently, suppressing epithelial-to-mesenchymal transition (EMT) has been considered a promising strategy for treating metastatic cancer, especially drug-resistant metastatic cancer. The present study aimed to evaluate the antimetastatic effect of Coptidis Rhizoma, as well as the potential underlying mechanisms, using a 5-fluorouracil-resistant colon tumor cell model (HCT116/R). Coptidis Rhizoma 30% ethanol extract (CRE) significantly inhibited HCT116/R cells migration and invasion. CRE effectively inhibited EMT in HCT116/R cells by upregulating the expression of an epithelial marker (E-cadherin) and downregulating the expression of mesenchymal markers (vimentin, Snail, and ZEB2) at both the protein and gene levels. Immunofluorescence assays also confirmed consistent patterns in the levels of E-cadherin and vimentin. In addition, the anti-EMT activity of CRE and its related effects were associated with the CRE-mediated suppression of the TGF-β pathway, as shown by changes in the levels of downstream molecules (phosphorylated Akt and p38), and inhibition of migration, invasion, and protein expression of TGF-β after treatment/cotreatment with a TGF-β inhibitor (SB431542). In conclusion, Coptidis Rhizoma exerts an antimetastatic effect, especially in the treatment of drug-resistant cancer, and the possible mechanisms are associated with inhibiting EMT via TGF-β signaling. Thus, Coptidis Rhizoma will likely become a potential therapeutic candidate for simultaneously mitigating drug resistance and metastasis in CRC. |
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spelling | doaj.art-696fec25c1aa450d8434538953fa459d2022-12-22T03:27:32ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-06-011310.3389/fphar.2022.909331909331Coptidis Rhizoma Suppresses Metastatic Behavior by Inhibiting TGF-β-Mediated Epithelial-Mesenchymal Transition in 5-FU-Resistant HCT116 CellsYong-Hwi Kang0Jing-Hua Wang1Jin-Seok Lee2Nam-Hun Lee3Nam-Hun Lee4Chang-Gue Son5Institute of Bioscience and Integrative Medicine, Daejeon Oriental Hospital of Daejeon University, Daejeon, South KoreaInstitute of Bioscience and Integrative Medicine, Daejeon Oriental Hospital of Daejeon University, Daejeon, South KoreaInstitute of Bioscience and Integrative Medicine, Daejeon Oriental Hospital of Daejeon University, Daejeon, South KoreaInstitute of Bioscience and Integrative Medicine, Daejeon Oriental Hospital of Daejeon University, Daejeon, South KoreaDepartment of Clinical Oncology, Cheonan Oriental Hospital of Daejeon University, Cheonan-si, South KoreaInstitute of Bioscience and Integrative Medicine, Daejeon Oriental Hospital of Daejeon University, Daejeon, South KoreaColorectal cancer (CRC) is the second most lethal malignancy worldwide. The high mortality rate of CRC is largely due to cancer metastasis. Recently, suppressing epithelial-to-mesenchymal transition (EMT) has been considered a promising strategy for treating metastatic cancer, especially drug-resistant metastatic cancer. The present study aimed to evaluate the antimetastatic effect of Coptidis Rhizoma, as well as the potential underlying mechanisms, using a 5-fluorouracil-resistant colon tumor cell model (HCT116/R). Coptidis Rhizoma 30% ethanol extract (CRE) significantly inhibited HCT116/R cells migration and invasion. CRE effectively inhibited EMT in HCT116/R cells by upregulating the expression of an epithelial marker (E-cadherin) and downregulating the expression of mesenchymal markers (vimentin, Snail, and ZEB2) at both the protein and gene levels. Immunofluorescence assays also confirmed consistent patterns in the levels of E-cadherin and vimentin. In addition, the anti-EMT activity of CRE and its related effects were associated with the CRE-mediated suppression of the TGF-β pathway, as shown by changes in the levels of downstream molecules (phosphorylated Akt and p38), and inhibition of migration, invasion, and protein expression of TGF-β after treatment/cotreatment with a TGF-β inhibitor (SB431542). In conclusion, Coptidis Rhizoma exerts an antimetastatic effect, especially in the treatment of drug-resistant cancer, and the possible mechanisms are associated with inhibiting EMT via TGF-β signaling. Thus, Coptidis Rhizoma will likely become a potential therapeutic candidate for simultaneously mitigating drug resistance and metastasis in CRC.https://www.frontiersin.org/articles/10.3389/fphar.2022.909331/fullcolorectal cancermetastasis5-fluorouracilEMTcoptidis rhizomaTGF-β |
spellingShingle | Yong-Hwi Kang Jing-Hua Wang Jin-Seok Lee Nam-Hun Lee Nam-Hun Lee Chang-Gue Son Coptidis Rhizoma Suppresses Metastatic Behavior by Inhibiting TGF-β-Mediated Epithelial-Mesenchymal Transition in 5-FU-Resistant HCT116 Cells Frontiers in Pharmacology colorectal cancer metastasis 5-fluorouracil EMT coptidis rhizoma TGF-β |
title | Coptidis Rhizoma Suppresses Metastatic Behavior by Inhibiting TGF-β-Mediated Epithelial-Mesenchymal Transition in 5-FU-Resistant HCT116 Cells |
title_full | Coptidis Rhizoma Suppresses Metastatic Behavior by Inhibiting TGF-β-Mediated Epithelial-Mesenchymal Transition in 5-FU-Resistant HCT116 Cells |
title_fullStr | Coptidis Rhizoma Suppresses Metastatic Behavior by Inhibiting TGF-β-Mediated Epithelial-Mesenchymal Transition in 5-FU-Resistant HCT116 Cells |
title_full_unstemmed | Coptidis Rhizoma Suppresses Metastatic Behavior by Inhibiting TGF-β-Mediated Epithelial-Mesenchymal Transition in 5-FU-Resistant HCT116 Cells |
title_short | Coptidis Rhizoma Suppresses Metastatic Behavior by Inhibiting TGF-β-Mediated Epithelial-Mesenchymal Transition in 5-FU-Resistant HCT116 Cells |
title_sort | coptidis rhizoma suppresses metastatic behavior by inhibiting tgf β mediated epithelial mesenchymal transition in 5 fu resistant hct116 cells |
topic | colorectal cancer metastasis 5-fluorouracil EMT coptidis rhizoma TGF-β |
url | https://www.frontiersin.org/articles/10.3389/fphar.2022.909331/full |
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