Novel Inhibitor for Downstream Targeting of Transforming Growth Factor-β Signaling to Suppress Epithelial to Mesenchymal Transition and Cell Migration
Cancer metastasis accounts for most of the mortality associated with solid tumors. However, antimetastatic drugs are not available on the market. One of the important biological events leading to metastasis is the epithelial to mesenchymal transition (EMT) induced by cytokines, namely transforming g...
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MDPI AG
2022-05-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/9/5047 |
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| author | Tsugumasa Toma Hiroshi Tateishi Kensaku Kawakami Taha F. S. Ali Masahiro Kamo Kazuaki Monde Yuta Nakashima Mikako Fujita Masami Otsuka |
| author_facet | Tsugumasa Toma Hiroshi Tateishi Kensaku Kawakami Taha F. S. Ali Masahiro Kamo Kazuaki Monde Yuta Nakashima Mikako Fujita Masami Otsuka |
| author_sort | Tsugumasa Toma |
| collection | DOAJ |
| description | Cancer metastasis accounts for most of the mortality associated with solid tumors. However, antimetastatic drugs are not available on the market. One of the important biological events leading to metastasis is the epithelial to mesenchymal transition (EMT) induced by cytokines, namely transforming growth-factor-β (TGF-β). Although several classes of inhibitors targeting TGF-β and its receptor have been developed, they have shown profound clinical side effects. We focused on our synthetic compound, HPH-15, which has shown anti-fibrotic activity via the blockade of the TGF-β Smad-dependent signaling. In this study, 10 μM of HPH-15 was found to exhibit anti-cell migration and anti-EMT activities in non-small-cell lung cancer (NSCLC) cells. Although higher concentrations are required, the anti-EMT activity of HPH-15 has also been observed in 3D-cultured NSCLC cells. A mechanistic study showed that HPH-15 inhibits downstream TGF-β signaling. This downstream inhibition blocks the expression of cytokines such as TGF-β, leading to the next cycle of Smad-dependent and -independent signaling. HPH-15 has AMPK-activation activity, but a relationship between AMPK activation and anti-EMT/cell migration was not observed. Taken together, HPH-15 may lead to the development of antimetastatic drugs with a new mechanism of action. |
| first_indexed | 2024-03-10T04:04:22Z |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T04:04:22Z |
| publishDate | 2022-05-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-73b03f37513e44cd978bdb5e10e29aa02023-11-23T08:26:17ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-05-01239504710.3390/ijms23095047Novel Inhibitor for Downstream Targeting of Transforming Growth Factor-β Signaling to Suppress Epithelial to Mesenchymal Transition and Cell MigrationTsugumasa Toma0Hiroshi Tateishi1Kensaku Kawakami2Taha F. S. Ali3Masahiro Kamo4Kazuaki Monde5Yuta Nakashima6Mikako Fujita7Masami Otsuka8Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto 862-0973, JapanMedicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto 862-0973, JapanGraduate School of Science and Technology, Kumamoto University, Kumamoto 860-8555, JapanMedicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto 862-0973, JapanMedicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto 862-0973, JapanDepartment of Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, JapanFaculty of Advanced Science and Technology, Kumamoto University, Kumamoto 860-8555, JapanMedicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto 862-0973, JapanMedicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto 862-0973, JapanCancer metastasis accounts for most of the mortality associated with solid tumors. However, antimetastatic drugs are not available on the market. One of the important biological events leading to metastasis is the epithelial to mesenchymal transition (EMT) induced by cytokines, namely transforming growth-factor-β (TGF-β). Although several classes of inhibitors targeting TGF-β and its receptor have been developed, they have shown profound clinical side effects. We focused on our synthetic compound, HPH-15, which has shown anti-fibrotic activity via the blockade of the TGF-β Smad-dependent signaling. In this study, 10 μM of HPH-15 was found to exhibit anti-cell migration and anti-EMT activities in non-small-cell lung cancer (NSCLC) cells. Although higher concentrations are required, the anti-EMT activity of HPH-15 has also been observed in 3D-cultured NSCLC cells. A mechanistic study showed that HPH-15 inhibits downstream TGF-β signaling. This downstream inhibition blocks the expression of cytokines such as TGF-β, leading to the next cycle of Smad-dependent and -independent signaling. HPH-15 has AMPK-activation activity, but a relationship between AMPK activation and anti-EMT/cell migration was not observed. Taken together, HPH-15 may lead to the development of antimetastatic drugs with a new mechanism of action.https://www.mdpi.com/1422-0067/23/9/5047anti-cell migrationanti-epithelial to mesenchymal transition (EMT)transforming growth factor-β (TGF-β)non-small-cell lung cancer (NSCLC) cellsSmad |
| spellingShingle | Tsugumasa Toma Hiroshi Tateishi Kensaku Kawakami Taha F. S. Ali Masahiro Kamo Kazuaki Monde Yuta Nakashima Mikako Fujita Masami Otsuka Novel Inhibitor for Downstream Targeting of Transforming Growth Factor-β Signaling to Suppress Epithelial to Mesenchymal Transition and Cell Migration International Journal of Molecular Sciences anti-cell migration anti-epithelial to mesenchymal transition (EMT) transforming growth factor-β (TGF-β) non-small-cell lung cancer (NSCLC) cells Smad |
| title | Novel Inhibitor for Downstream Targeting of Transforming Growth Factor-β Signaling to Suppress Epithelial to Mesenchymal Transition and Cell Migration |
| title_full | Novel Inhibitor for Downstream Targeting of Transforming Growth Factor-β Signaling to Suppress Epithelial to Mesenchymal Transition and Cell Migration |
| title_fullStr | Novel Inhibitor for Downstream Targeting of Transforming Growth Factor-β Signaling to Suppress Epithelial to Mesenchymal Transition and Cell Migration |
| title_full_unstemmed | Novel Inhibitor for Downstream Targeting of Transforming Growth Factor-β Signaling to Suppress Epithelial to Mesenchymal Transition and Cell Migration |
| title_short | Novel Inhibitor for Downstream Targeting of Transforming Growth Factor-β Signaling to Suppress Epithelial to Mesenchymal Transition and Cell Migration |
| title_sort | novel inhibitor for downstream targeting of transforming growth factor β signaling to suppress epithelial to mesenchymal transition and cell migration |
| topic | anti-cell migration anti-epithelial to mesenchymal transition (EMT) transforming growth factor-β (TGF-β) non-small-cell lung cancer (NSCLC) cells Smad |
| url | https://www.mdpi.com/1422-0067/23/9/5047 |
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