Elaiophylin Inhibits Tumorigenesis of Human Uveal Melanoma by Suppressing Mitophagy and Inducing Oxidative Stress via Modulating SIRT1/FoxO3a Signaling
Uveal melanoma (UM) is the most common primary intraocular tumor in adults, which is associated with poor prognosis. Up to 50% of UM patients develop metastasis. Therapeutics that have proven effective in cutaneous melanoma have little success in treating UM, possibly due to its low mutational burde...
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| Format: | Article |
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Frontiers Media S.A.
2022-03-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.788496/full |
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| author | Xue Zhu Xue Zhu Wenjun Zou Xinmin Meng Xinmin Meng Jiali Ji Xun Wang Hong Shu Yuan Chen Yuan Chen Donghui Pan Donghui Pan Ke Wang Ke Wang Fanfan Zhou |
| author_facet | Xue Zhu Xue Zhu Wenjun Zou Xinmin Meng Xinmin Meng Jiali Ji Xun Wang Hong Shu Yuan Chen Yuan Chen Donghui Pan Donghui Pan Ke Wang Ke Wang Fanfan Zhou |
| author_sort | Xue Zhu |
| collection | DOAJ |
| description | Uveal melanoma (UM) is the most common primary intraocular tumor in adults, which is associated with poor prognosis. Up to 50% of UM patients develop metastasis. Therapeutics that have proven effective in cutaneous melanoma have little success in treating UM, possibly due to its low mutational burden. Therefore, new drug therapies are highly desired for UM. Our in vitro studies showed that Elaiophylin, a late-stage autophagy inhibitor, exhibited an outstanding anticancer activity in human UM cell lines and human UM primary cells through suppressing mitophagy, inducing oxidative stress and leading to autophagic cell death. Our mechanistic study revealed that Elaiophylin exerted its effect by down-regulating SIRT1 and thus influencing deacetylation and mitochondrial localization of FoxO3a. In our confirmatory experiments, SRT1720, a SIRT1 specific activator, could attenuate Elaiophylin-induced inhibition of mitophagy and elevation of oxidative stress, and such effects was partly reversed by FoxO3a knockdown. Our further in vivo studies showed that Elaiophylin dramatically inhibited tumor growth in the human UM xenograft mouse model, which was accompanied with a decreased SIRT1 expression. Thus, the current study is the first to demonstrate that Elaiophylin has a potent anti-cancer effect against UM, which activity is possibly mediated through regulating SIRT1-FoxO3a signaling axis. And Elaiophylin may be a new and promising drug candidate to treat human UM. |
| first_indexed | 2024-12-13T20:24:01Z |
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| id | doaj.art-9df6ab0e2ce9404582dd64ce41273446 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-13T20:24:01Z |
| publishDate | 2022-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-9df6ab0e2ce9404582dd64ce412734462022-12-21T23:32:36ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-03-011210.3389/fonc.2022.788496788496Elaiophylin Inhibits Tumorigenesis of Human Uveal Melanoma by Suppressing Mitophagy and Inducing Oxidative Stress via Modulating SIRT1/FoxO3a SignalingXue Zhu0Xue Zhu1Wenjun Zou2Xinmin Meng3Xinmin Meng4Jiali Ji5Xun Wang6Hong Shu7Yuan Chen8Yuan Chen9Donghui Pan10Donghui Pan11Ke Wang12Ke Wang13Fanfan Zhou14National Health Commission (NHC) Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, ChinaDepartment of Radiopharmaceuticals, School of Pharmacy, Nanjing Medical University, Nanjing, ChinaDepartment of Ophthalmology, The Affiliated Wuxi No.2 People’s Hospital of Nanjing Medical University, Wuxi, ChinaDepartment of Respiratory and Critical Care Medicine, The Affiliated Wuxi No.2 People’s Hospital of Nanjing Medical University, Wuxi, ChinaDepartment of Laboratory Medicine, Cancer Medical College of Guangxi Medical University, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, ChinaDepartment of Respiratory and Critical Care Medicine, The Affiliated Wuxi No.2 People’s Hospital of Nanjing Medical University, Wuxi, ChinaDepartment of Respiratory and Critical Care Medicine, The Affiliated Wuxi No.2 People’s Hospital of Nanjing Medical University, Wuxi, ChinaDepartment of Laboratory Medicine, Cancer Medical College of Guangxi Medical University, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, ChinaNational Health Commission (NHC) Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, ChinaDepartment of Radiopharmaceuticals, School of Pharmacy, Nanjing Medical University, Nanjing, ChinaNational Health Commission (NHC) Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, ChinaDepartment of Radiopharmaceuticals, School of Pharmacy, Nanjing Medical University, Nanjing, ChinaNational Health Commission (NHC) Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, ChinaDepartment of Radiopharmaceuticals, School of Pharmacy, Nanjing Medical University, Nanjing, ChinaSydney Pharmacy School, The University of Sydney, Sydney, NSW, AustraliaUveal melanoma (UM) is the most common primary intraocular tumor in adults, which is associated with poor prognosis. Up to 50% of UM patients develop metastasis. Therapeutics that have proven effective in cutaneous melanoma have little success in treating UM, possibly due to its low mutational burden. Therefore, new drug therapies are highly desired for UM. Our in vitro studies showed that Elaiophylin, a late-stage autophagy inhibitor, exhibited an outstanding anticancer activity in human UM cell lines and human UM primary cells through suppressing mitophagy, inducing oxidative stress and leading to autophagic cell death. Our mechanistic study revealed that Elaiophylin exerted its effect by down-regulating SIRT1 and thus influencing deacetylation and mitochondrial localization of FoxO3a. In our confirmatory experiments, SRT1720, a SIRT1 specific activator, could attenuate Elaiophylin-induced inhibition of mitophagy and elevation of oxidative stress, and such effects was partly reversed by FoxO3a knockdown. Our further in vivo studies showed that Elaiophylin dramatically inhibited tumor growth in the human UM xenograft mouse model, which was accompanied with a decreased SIRT1 expression. Thus, the current study is the first to demonstrate that Elaiophylin has a potent anti-cancer effect against UM, which activity is possibly mediated through regulating SIRT1-FoxO3a signaling axis. And Elaiophylin may be a new and promising drug candidate to treat human UM.https://www.frontiersin.org/articles/10.3389/fonc.2022.788496/fulluveal melanomaelaiophylinmitophagyoxidative stressSIRT1/FoxO3a signaling |
| spellingShingle | Xue Zhu Xue Zhu Wenjun Zou Xinmin Meng Xinmin Meng Jiali Ji Xun Wang Hong Shu Yuan Chen Yuan Chen Donghui Pan Donghui Pan Ke Wang Ke Wang Fanfan Zhou Elaiophylin Inhibits Tumorigenesis of Human Uveal Melanoma by Suppressing Mitophagy and Inducing Oxidative Stress via Modulating SIRT1/FoxO3a Signaling Frontiers in Oncology uveal melanoma elaiophylin mitophagy oxidative stress SIRT1/FoxO3a signaling |
| title | Elaiophylin Inhibits Tumorigenesis of Human Uveal Melanoma by Suppressing Mitophagy and Inducing Oxidative Stress via Modulating SIRT1/FoxO3a Signaling |
| title_full | Elaiophylin Inhibits Tumorigenesis of Human Uveal Melanoma by Suppressing Mitophagy and Inducing Oxidative Stress via Modulating SIRT1/FoxO3a Signaling |
| title_fullStr | Elaiophylin Inhibits Tumorigenesis of Human Uveal Melanoma by Suppressing Mitophagy and Inducing Oxidative Stress via Modulating SIRT1/FoxO3a Signaling |
| title_full_unstemmed | Elaiophylin Inhibits Tumorigenesis of Human Uveal Melanoma by Suppressing Mitophagy and Inducing Oxidative Stress via Modulating SIRT1/FoxO3a Signaling |
| title_short | Elaiophylin Inhibits Tumorigenesis of Human Uveal Melanoma by Suppressing Mitophagy and Inducing Oxidative Stress via Modulating SIRT1/FoxO3a Signaling |
| title_sort | elaiophylin inhibits tumorigenesis of human uveal melanoma by suppressing mitophagy and inducing oxidative stress via modulating sirt1 foxo3a signaling |
| topic | uveal melanoma elaiophylin mitophagy oxidative stress SIRT1/FoxO3a signaling |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.788496/full |
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