Mefloquine Inhibits Esophageal Squamous Cell Carcinoma Tumor Growth by Inducing Mitochondrial Autophagy

Yifei Xie; Jing Zhang; Bingbing Lu; Zhuo Bao; Jimin Zhao; Xianyu Lu; Yaxing Wei; Ke Yao; Yanan Jiang; Qiang Yuan; Xiaofan Zhang; Bo Li; Xinhuan Chen; Zigang Dong; Kangdong Liu

doi:10.3389/fonc.2020.01217

Mefloquine Inhibits Esophageal Squamous Cell Carcinoma Tumor Growth by Inducing Mitochondrial Autophagy

Yifei Xie, Jing Zhang, Bingbing Lu, Zhuo Bao, Jimin Zhao, Xianyu Lu, Yaxing Wei, Ke Yao, Yanan Jiang, Qiang Yuan, Xiaofan Zhang, Bo Li, Xinhuan Chen, Zigang Dong, Kangdong Liu

Research output: Contribution to journal › Article › peer-review

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Abstract

Esophageal squamous cell carcinoma (ESCC) has a worldwide impact on human health, due to its high incidence and mortality. Therefore, identifying compounds to increase patients' survival rate is urgently needed. Mefloquine (MQ) is an FDA-approved anti-malarial drug, which has been reported to inhibit cellular proliferation in several cancers. However, the anti-tumor activities of the drug have not yet been completely defined. In this study, mass spectrometry was employed to profile proteome changes in ESCC cells after MQ treatment. Sub-cellular localization and gene ontology term enrichment analysis suggested that MQ treatment mainly affect mitochondria. The KEGG pathway enrichment map of down-regulated pathways and Venn diagram indicated that all of the top five down regulated signaling pathways contain four key mitochondrial proteins (succinate dehydrogenase complex subunit C (SDHC), succinate dehydrogenase complex subunit D, mitochondrially encoded cytochrome c oxidase III and NADH: ubiquinone oxidoreductase subunit V3). Meanwhile, mitochondrial autophagy was observed in MQ-treated KYSE150 cells. More importantly, patient-derived xenograft mouse models of ESCC with SDHC high expression were more sensitive to MQ treatment than low SDHC-expressing xenografts. Taken together, mefloquine inhibits ESCC tumor growth by inducing mitochondrial autophagy and SDHC plays a vital role in MQ-induced anti-tumor effect on ESCC.

Original language	English (US)
Article number	1217
Journal	Frontiers in Oncology
Volume	10
DOIs	https://doi.org/10.3389/fonc.2020.01217
State	Published - Jul 28 2020
Externally published	Yes

Bibliographical note

Funding Information:
This research was funded by the National Natural Science Foundations of China (grant number 81872335), National Natural Science Youth Foundation (grant number 81902486), National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China (No. 2018ZX09711002), the Natural Science Foundation of Henan (grant number 161100510300), and China Scholarship Council.

Funding Information:
Funding. This research was funded by the National Natural Science Foundations of China (grant number 81872335), National Natural Science Youth Foundation (grant number 81902486), National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China (No. 2018ZX09711002), the Natural Science Foundation of Henan (grant number 161100510300), and China Scholarship Council.

Publisher Copyright:
© Copyright © 2020 Xie, Zhang, Lu, Bao, Zhao, Lu, Wei, Yao, Jiang, Yuan, Zhang, Li, Chen, Dong and Liu.

Keywords

autophagy
esophageal squamous cell carcinoma (ESCC)
mefloquine (MQ)
mitochondria
succinate dehydrogenase complex subunit C (SDHC)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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@article{d8f41941dbce41069288728d0d78db90,

title = "Mefloquine Inhibits Esophageal Squamous Cell Carcinoma Tumor Growth by Inducing Mitochondrial Autophagy",

abstract = "Esophageal squamous cell carcinoma (ESCC) has a worldwide impact on human health, due to its high incidence and mortality. Therefore, identifying compounds to increase patients' survival rate is urgently needed. Mefloquine (MQ) is an FDA-approved anti-malarial drug, which has been reported to inhibit cellular proliferation in several cancers. However, the anti-tumor activities of the drug have not yet been completely defined. In this study, mass spectrometry was employed to profile proteome changes in ESCC cells after MQ treatment. Sub-cellular localization and gene ontology term enrichment analysis suggested that MQ treatment mainly affect mitochondria. The KEGG pathway enrichment map of down-regulated pathways and Venn diagram indicated that all of the top five down regulated signaling pathways contain four key mitochondrial proteins (succinate dehydrogenase complex subunit C (SDHC), succinate dehydrogenase complex subunit D, mitochondrially encoded cytochrome c oxidase III and NADH: ubiquinone oxidoreductase subunit V3). Meanwhile, mitochondrial autophagy was observed in MQ-treated KYSE150 cells. More importantly, patient-derived xenograft mouse models of ESCC with SDHC high expression were more sensitive to MQ treatment than low SDHC-expressing xenografts. Taken together, mefloquine inhibits ESCC tumor growth by inducing mitochondrial autophagy and SDHC plays a vital role in MQ-induced anti-tumor effect on ESCC.",

keywords = "autophagy, esophageal squamous cell carcinoma (ESCC), mefloquine (MQ), mitochondria, succinate dehydrogenase complex subunit C (SDHC)",

author = "Yifei Xie and Jing Zhang and Bingbing Lu and Zhuo Bao and Jimin Zhao and Xianyu Lu and Yaxing Wei and Ke Yao and Yanan Jiang and Qiang Yuan and Xiaofan Zhang and Bo Li and Xinhuan Chen and Zigang Dong and Kangdong Liu",

note = "Funding Information: This research was funded by the National Natural Science Foundations of China (grant number 81872335), National Natural Science Youth Foundation (grant number 81902486), National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China (No. 2018ZX09711002), the Natural Science Foundation of Henan (grant number 161100510300), and China Scholarship Council. Funding Information: Funding. This research was funded by the National Natural Science Foundations of China (grant number 81872335), National Natural Science Youth Foundation (grant number 81902486), National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China (No. 2018ZX09711002), the Natural Science Foundation of Henan (grant number 161100510300), and China Scholarship Council. Publisher Copyright: {\textcopyright} Copyright {\textcopyright} 2020 Xie, Zhang, Lu, Bao, Zhao, Lu, Wei, Yao, Jiang, Yuan, Zhang, Li, Chen, Dong and Liu.",

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AU - Xie, Yifei

AU - Zhang, Jing

AU - Lu, Bingbing

AU - Bao, Zhuo

AU - Zhao, Jimin

AU - Lu, Xianyu

AU - Wei, Yaxing

AU - Yao, Ke

AU - Jiang, Yanan

AU - Yuan, Qiang

AU - Zhang, Xiaofan

AU - Li, Bo

AU - Chen, Xinhuan

AU - Dong, Zigang

AU - Liu, Kangdong

N1 - Funding Information: This research was funded by the National Natural Science Foundations of China (grant number 81872335), National Natural Science Youth Foundation (grant number 81902486), National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China (No. 2018ZX09711002), the Natural Science Foundation of Henan (grant number 161100510300), and China Scholarship Council. Funding Information: Funding. This research was funded by the National Natural Science Foundations of China (grant number 81872335), National Natural Science Youth Foundation (grant number 81902486), National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China (No. 2018ZX09711002), the Natural Science Foundation of Henan (grant number 161100510300), and China Scholarship Council. Publisher Copyright: © Copyright © 2020 Xie, Zhang, Lu, Bao, Zhao, Lu, Wei, Yao, Jiang, Yuan, Zhang, Li, Chen, Dong and Liu.

PY - 2020/7/28

Y1 - 2020/7/28

N2 - Esophageal squamous cell carcinoma (ESCC) has a worldwide impact on human health, due to its high incidence and mortality. Therefore, identifying compounds to increase patients' survival rate is urgently needed. Mefloquine (MQ) is an FDA-approved anti-malarial drug, which has been reported to inhibit cellular proliferation in several cancers. However, the anti-tumor activities of the drug have not yet been completely defined. In this study, mass spectrometry was employed to profile proteome changes in ESCC cells after MQ treatment. Sub-cellular localization and gene ontology term enrichment analysis suggested that MQ treatment mainly affect mitochondria. The KEGG pathway enrichment map of down-regulated pathways and Venn diagram indicated that all of the top five down regulated signaling pathways contain four key mitochondrial proteins (succinate dehydrogenase complex subunit C (SDHC), succinate dehydrogenase complex subunit D, mitochondrially encoded cytochrome c oxidase III and NADH: ubiquinone oxidoreductase subunit V3). Meanwhile, mitochondrial autophagy was observed in MQ-treated KYSE150 cells. More importantly, patient-derived xenograft mouse models of ESCC with SDHC high expression were more sensitive to MQ treatment than low SDHC-expressing xenografts. Taken together, mefloquine inhibits ESCC tumor growth by inducing mitochondrial autophagy and SDHC plays a vital role in MQ-induced anti-tumor effect on ESCC.

AB - Esophageal squamous cell carcinoma (ESCC) has a worldwide impact on human health, due to its high incidence and mortality. Therefore, identifying compounds to increase patients' survival rate is urgently needed. Mefloquine (MQ) is an FDA-approved anti-malarial drug, which has been reported to inhibit cellular proliferation in several cancers. However, the anti-tumor activities of the drug have not yet been completely defined. In this study, mass spectrometry was employed to profile proteome changes in ESCC cells after MQ treatment. Sub-cellular localization and gene ontology term enrichment analysis suggested that MQ treatment mainly affect mitochondria. The KEGG pathway enrichment map of down-regulated pathways and Venn diagram indicated that all of the top five down regulated signaling pathways contain four key mitochondrial proteins (succinate dehydrogenase complex subunit C (SDHC), succinate dehydrogenase complex subunit D, mitochondrially encoded cytochrome c oxidase III and NADH: ubiquinone oxidoreductase subunit V3). Meanwhile, mitochondrial autophagy was observed in MQ-treated KYSE150 cells. More importantly, patient-derived xenograft mouse models of ESCC with SDHC high expression were more sensitive to MQ treatment than low SDHC-expressing xenografts. Taken together, mefloquine inhibits ESCC tumor growth by inducing mitochondrial autophagy and SDHC plays a vital role in MQ-induced anti-tumor effect on ESCC.

KW - autophagy

KW - esophageal squamous cell carcinoma (ESCC)

KW - mefloquine (MQ)

KW - mitochondria

KW - succinate dehydrogenase complex subunit C (SDHC)

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ER -

Mefloquine Inhibits Esophageal Squamous Cell Carcinoma Tumor Growth by Inducing Mitochondrial Autophagy

Abstract

Bibliographical note

Keywords

UN SDGs

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