Urolithin A targets the AKT/WNK1 axis to induce autophagy and exert anti-tumor effects in cholangiocarcinoma
Urolithin A (UA; 3,8-dihydroxybenzo[c]chromen-6-one), a metabolite generated by intestinal bacteria during the biotransformation of ellagitannins, has gained considerable attention in treating several cancers. Cholangiocarcinoma (CCA) remains one of the most lethal cancers; it grows in a special env...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-09-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.963314/full |
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| author | Hidenori Sahashi Akihisa Kato Michihiro Yoshida Kazuki Hayashi Itaru Naitoh Yasuki Hori Makoto Natsume Naruomi Jinno Kenta Kachi Go Asano Tadashi Toyohara Yusuke Kito Sudhakar Ammanamanchi Hiromi Kataoka |
| author_facet | Hidenori Sahashi Akihisa Kato Michihiro Yoshida Kazuki Hayashi Itaru Naitoh Yasuki Hori Makoto Natsume Naruomi Jinno Kenta Kachi Go Asano Tadashi Toyohara Yusuke Kito Sudhakar Ammanamanchi Hiromi Kataoka |
| author_sort | Hidenori Sahashi |
| collection | DOAJ |
| description | Urolithin A (UA; 3,8-dihydroxybenzo[c]chromen-6-one), a metabolite generated by intestinal bacteria during the biotransformation of ellagitannins, has gained considerable attention in treating several cancers. Cholangiocarcinoma (CCA) remains one of the most lethal cancers; it grows in a special environment constantly exposed to both blood and bile. Since UA is known to undergo enterohepatic recirculation, we hypothesized that UA might have significant antitumor effects in CCA. Here, we investigated the therapeutic potential of UA in CCA and aimed to elucidate its mechanisms, including autophagy. UA treatment inhibited cell proliferation and induced G2/M phase cell cycle arrest in CCA cells. UA also suppressed cell migration and invasion, but did not cause apoptosis. Furthermore, Western blotting and immunocytochemistry demonstrated increased LC3-II accumulation, while electron microscopy demonstrated induced autophagosomes after UA treatment, suggesting that UA upregulated autophagy in CCA cells. In xenograft mice treated with UA, tumor growth was inhibited with increased LC3-II levels. On the other hand, phospho-kinase array demonstrated downregulation of the AKT/WNK1 pathway. LC3-II expression was elevated in WNK1 knocked down cells, indicating that WNK1 is the key signal for regulating autophagy. Thus, UA exerted antitumor effects by suppressing the AKT/WNK1 signaling pathway and inducing autophagy. In conclusion, UA, a natural, well-tolerated compound, may be a promising therapeutic candidate for advanced CCA. |
| first_indexed | 2024-04-12T04:33:28Z |
| format | Article |
| id | doaj.art-723f98a57ed148ebb30f6514e67af4f6 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-12T04:33:28Z |
| publishDate | 2022-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-723f98a57ed148ebb30f6514e67af4f62022-12-22T03:47:52ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-09-011210.3389/fonc.2022.963314963314Urolithin A targets the AKT/WNK1 axis to induce autophagy and exert anti-tumor effects in cholangiocarcinomaHidenori Sahashi0Akihisa Kato1Michihiro Yoshida2Kazuki Hayashi3Itaru Naitoh4Yasuki Hori5Makoto Natsume6Naruomi Jinno7Kenta Kachi8Go Asano9Tadashi Toyohara10Yusuke Kito11Sudhakar Ammanamanchi12Hiromi Kataoka13Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, Nagoya, JapanDepartment of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, Nagoya, JapanDepartment of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, Nagoya, JapanDepartment of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, Nagoya, JapanDepartment of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, Nagoya, JapanDepartment of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, Nagoya, JapanDepartment of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, Nagoya, JapanDepartment of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, Nagoya, JapanDepartment of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, Nagoya, JapanDepartment of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, Nagoya, JapanDepartment of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, Nagoya, JapanDepartment of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, Nagoya, JapanDepartment of Internal Medicine, University of Arizona College of Medicine, Phoenix, AZ, United StatesDepartment of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, Nagoya, JapanUrolithin A (UA; 3,8-dihydroxybenzo[c]chromen-6-one), a metabolite generated by intestinal bacteria during the biotransformation of ellagitannins, has gained considerable attention in treating several cancers. Cholangiocarcinoma (CCA) remains one of the most lethal cancers; it grows in a special environment constantly exposed to both blood and bile. Since UA is known to undergo enterohepatic recirculation, we hypothesized that UA might have significant antitumor effects in CCA. Here, we investigated the therapeutic potential of UA in CCA and aimed to elucidate its mechanisms, including autophagy. UA treatment inhibited cell proliferation and induced G2/M phase cell cycle arrest in CCA cells. UA also suppressed cell migration and invasion, but did not cause apoptosis. Furthermore, Western blotting and immunocytochemistry demonstrated increased LC3-II accumulation, while electron microscopy demonstrated induced autophagosomes after UA treatment, suggesting that UA upregulated autophagy in CCA cells. In xenograft mice treated with UA, tumor growth was inhibited with increased LC3-II levels. On the other hand, phospho-kinase array demonstrated downregulation of the AKT/WNK1 pathway. LC3-II expression was elevated in WNK1 knocked down cells, indicating that WNK1 is the key signal for regulating autophagy. Thus, UA exerted antitumor effects by suppressing the AKT/WNK1 signaling pathway and inducing autophagy. In conclusion, UA, a natural, well-tolerated compound, may be a promising therapeutic candidate for advanced CCA.https://www.frontiersin.org/articles/10.3389/fonc.2022.963314/fullUrolithin AUAcholangiocarcinomaautophagyWNK1 |
| spellingShingle | Hidenori Sahashi Akihisa Kato Michihiro Yoshida Kazuki Hayashi Itaru Naitoh Yasuki Hori Makoto Natsume Naruomi Jinno Kenta Kachi Go Asano Tadashi Toyohara Yusuke Kito Sudhakar Ammanamanchi Hiromi Kataoka Urolithin A targets the AKT/WNK1 axis to induce autophagy and exert anti-tumor effects in cholangiocarcinoma Frontiers in Oncology Urolithin A UA cholangiocarcinoma autophagy WNK1 |
| title | Urolithin A targets the AKT/WNK1 axis to induce autophagy and exert anti-tumor effects in cholangiocarcinoma |
| title_full | Urolithin A targets the AKT/WNK1 axis to induce autophagy and exert anti-tumor effects in cholangiocarcinoma |
| title_fullStr | Urolithin A targets the AKT/WNK1 axis to induce autophagy and exert anti-tumor effects in cholangiocarcinoma |
| title_full_unstemmed | Urolithin A targets the AKT/WNK1 axis to induce autophagy and exert anti-tumor effects in cholangiocarcinoma |
| title_short | Urolithin A targets the AKT/WNK1 axis to induce autophagy and exert anti-tumor effects in cholangiocarcinoma |
| title_sort | urolithin a targets the akt wnk1 axis to induce autophagy and exert anti tumor effects in cholangiocarcinoma |
| topic | Urolithin A UA cholangiocarcinoma autophagy WNK1 |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.963314/full |
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