Ipriflavone Suppresses Growth of Esophageal Squamous Cell Carcinoma Through Inhibiting mTOR In Vitro and In Vivo
Ipriflavone, a synthetic isoflavone that inhibits osteoclastic bone resorption, has been used clinically for the treatment of osteoporosis. However, the anticancer activity of Ipriflavone and its molecular mechanisms in the context of esophageal squamous cell carcinoma (ESCC) have not been investiga...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-06-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2021.648809/full |
| _version_ | 1818664075175919616 |
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| author | Xiaodan Shi Yuanyuan Zhang Yuanyuan Zhang Xiaomeng Xie Xiaomeng Xie Mengjun Pang Mengjun Pang Kyle Laster Jian Li Xinli Ma Kangdong Liu Kangdong Liu Kangdong Liu Kangdong Liu Kangdong Liu Zigang Dong Zigang Dong Zigang Dong Zigang Dong Zigang Dong Dong Joon Kim Dong Joon Kim Dong Joon Kim |
| author_facet | Xiaodan Shi Yuanyuan Zhang Yuanyuan Zhang Xiaomeng Xie Xiaomeng Xie Mengjun Pang Mengjun Pang Kyle Laster Jian Li Xinli Ma Kangdong Liu Kangdong Liu Kangdong Liu Kangdong Liu Kangdong Liu Zigang Dong Zigang Dong Zigang Dong Zigang Dong Zigang Dong Dong Joon Kim Dong Joon Kim Dong Joon Kim |
| author_sort | Xiaodan Shi |
| collection | DOAJ |
| description | Ipriflavone, a synthetic isoflavone that inhibits osteoclastic bone resorption, has been used clinically for the treatment of osteoporosis. However, the anticancer activity of Ipriflavone and its molecular mechanisms in the context of esophageal squamous cell carcinoma (ESCC) have not been investigated. In this study, we report that Ipriflavone is a novel mammalian target of rapamycin (mTOR) inhibitor that suppresses cell proliferation and induces cell apoptosis in ESCC cells. Ipriflavone inhibited anchorage-dependent and -independent growth of ESCC cells. Ipriflavone induced G1 phase cell cycle arrest and intrinsic cell apoptosis by activating caspase 3 and increasing the expression of cytochrome c. Based on the results of in vitro screening and cell-based assays, Ipriflavone inhibited mTOR signaling pathway through directly targeting mTOR. Knockdown of mTOR strongly inhibited the growth of ESCC cells, and the cell growth inhibitory effect exerted by Ipriflavone was found to be dependent upon mTOR signaling pathway. Remarkably, Ipriflavone strongly inhibited ESCC patient-derived xenograft tumor growth in an in vivo mouse model. Our findings suggest that Ipriflavone is an mTOR inhibitor that could be potentially useful for treating ESCC. |
| first_indexed | 2024-12-17T05:26:58Z |
| format | Article |
| id | doaj.art-087e9fae5bf743beb5daba9ce9022516 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-17T05:26:58Z |
| publishDate | 2021-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-087e9fae5bf743beb5daba9ce90225162022-12-21T22:01:49ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2021-06-011110.3389/fonc.2021.648809648809Ipriflavone Suppresses Growth of Esophageal Squamous Cell Carcinoma Through Inhibiting mTOR In Vitro and In VivoXiaodan Shi0Yuanyuan Zhang1Yuanyuan Zhang2Xiaomeng Xie3Xiaomeng Xie4Mengjun Pang5Mengjun Pang6Kyle Laster7Jian Li8Xinli Ma9Kangdong Liu10Kangdong Liu11Kangdong Liu12Kangdong Liu13Kangdong Liu14Zigang Dong15Zigang Dong16Zigang Dong17Zigang Dong18Zigang Dong19Dong Joon Kim20Dong Joon Kim21Dong Joon Kim22China-US (Henan) Hormel Cancer Institute, Zhengzhou, ChinaChina-US (Henan) Hormel Cancer Institute, Zhengzhou, ChinaDepartment of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, ChinaChina-US (Henan) Hormel Cancer Institute, Zhengzhou, ChinaDepartment of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, ChinaChina-US (Henan) Hormel Cancer Institute, Zhengzhou, ChinaDepartment of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, ChinaChina-US (Henan) Hormel Cancer Institute, Zhengzhou, ChinaChina-US (Henan) Hormel Cancer Institute, Zhengzhou, ChinaChina-US (Henan) Hormel Cancer Institute, Zhengzhou, ChinaChina-US (Henan) Hormel Cancer Institute, Zhengzhou, ChinaDepartment of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, ChinaThe Affiliated Cancer Hospital, Zhengzhou University, Zhengzhou, ChinaThe Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, ChinaInternational Joint Research Center of Cancer Chemoprevention, Zhengzhou, ChinaChina-US (Henan) Hormel Cancer Institute, Zhengzhou, ChinaDepartment of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, ChinaThe Affiliated Cancer Hospital, Zhengzhou University, Zhengzhou, ChinaThe Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, ChinaInternational Joint Research Center of Cancer Chemoprevention, Zhengzhou, ChinaChina-US (Henan) Hormel Cancer Institute, Zhengzhou, ChinaDepartment of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, ChinaThe Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, ChinaIpriflavone, a synthetic isoflavone that inhibits osteoclastic bone resorption, has been used clinically for the treatment of osteoporosis. However, the anticancer activity of Ipriflavone and its molecular mechanisms in the context of esophageal squamous cell carcinoma (ESCC) have not been investigated. In this study, we report that Ipriflavone is a novel mammalian target of rapamycin (mTOR) inhibitor that suppresses cell proliferation and induces cell apoptosis in ESCC cells. Ipriflavone inhibited anchorage-dependent and -independent growth of ESCC cells. Ipriflavone induced G1 phase cell cycle arrest and intrinsic cell apoptosis by activating caspase 3 and increasing the expression of cytochrome c. Based on the results of in vitro screening and cell-based assays, Ipriflavone inhibited mTOR signaling pathway through directly targeting mTOR. Knockdown of mTOR strongly inhibited the growth of ESCC cells, and the cell growth inhibitory effect exerted by Ipriflavone was found to be dependent upon mTOR signaling pathway. Remarkably, Ipriflavone strongly inhibited ESCC patient-derived xenograft tumor growth in an in vivo mouse model. Our findings suggest that Ipriflavone is an mTOR inhibitor that could be potentially useful for treating ESCC.https://www.frontiersin.org/articles/10.3389/fonc.2021.648809/fullpatient-derived xenograft (PDX)ESCCP70S6KmTORIpriflavone |
| spellingShingle | Xiaodan Shi Yuanyuan Zhang Yuanyuan Zhang Xiaomeng Xie Xiaomeng Xie Mengjun Pang Mengjun Pang Kyle Laster Jian Li Xinli Ma Kangdong Liu Kangdong Liu Kangdong Liu Kangdong Liu Kangdong Liu Zigang Dong Zigang Dong Zigang Dong Zigang Dong Zigang Dong Dong Joon Kim Dong Joon Kim Dong Joon Kim Ipriflavone Suppresses Growth of Esophageal Squamous Cell Carcinoma Through Inhibiting mTOR In Vitro and In Vivo Frontiers in Oncology patient-derived xenograft (PDX) ESCC P70S6K mTOR Ipriflavone |
| title | Ipriflavone Suppresses Growth of Esophageal Squamous Cell Carcinoma Through Inhibiting mTOR In Vitro and In Vivo |
| title_full | Ipriflavone Suppresses Growth of Esophageal Squamous Cell Carcinoma Through Inhibiting mTOR In Vitro and In Vivo |
| title_fullStr | Ipriflavone Suppresses Growth of Esophageal Squamous Cell Carcinoma Through Inhibiting mTOR In Vitro and In Vivo |
| title_full_unstemmed | Ipriflavone Suppresses Growth of Esophageal Squamous Cell Carcinoma Through Inhibiting mTOR In Vitro and In Vivo |
| title_short | Ipriflavone Suppresses Growth of Esophageal Squamous Cell Carcinoma Through Inhibiting mTOR In Vitro and In Vivo |
| title_sort | ipriflavone suppresses growth of esophageal squamous cell carcinoma through inhibiting mtor in vitro and in vivo |
| topic | patient-derived xenograft (PDX) ESCC P70S6K mTOR Ipriflavone |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2021.648809/full |
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