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DMFC (3,5-dimethyl-7H-furo[3,2-g]chromen-7-one) regulates Bim to trigger Bax and Bak activation to suppress drug-resistant human hepatoma

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Abstract

3,5-Dimethyl-7H-furo[3,2-g]chromen-7-one (DMFC) is a coumarin derivative with anti-cancer activity against human hepatoma cells, but the mechanisms underlying DMFC function in cancer suppression is unknown. In this study, we aimed at elucidating the molecular mechanisms underlying DMFC anti-cancer activity and determining whether DMFC is effective in suppression of drug-resistant human hepatocellular carcinoma. We show here that DMFC effectively suppresses both the parent and the multidrug-resistant hepatoma cell growth in vitro and DMFC suppresses hepatoma cell growth at least in part through inducing tumor cell apoptosis. In the molecular level, we observed that DMFC treatment decreases Bcl-2 level by a post-transcriptional mechanism and activates Bim transcription to increase Bim mRNA and protein level in hepatoma cells. Furthermore, co-immunoprecipitation studies revealed that DMFC-induced Bim interrupts interactions between Bcl-2 and Bax and between Mcl-1 and Bak, resulting in dissociation of Bax from Bcl-2 and Bak from Mcl-1 and subsequent activation of both Bax and Bak. Activation of Bax and Bak leads to mitochondrial outer membrane permeabilization and cytochrome c release. Consistent with its potent apoptosis-inducing activity, DMFC exhibited potent activity against the multidrug-resistant hepatoma xenograft growth in vivo. Therefore, we determine that DMFC suppresses hepatoma growth through decreasing Bcl-2 and increasing Bim to induce tumor cell apoptosis and hold great promise for further development as a therapeutic agent to treat chemoresistant hepatoma.

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Acknowledgements

This study is supported by National Natural Science Foundation of China (No. 31570811) Natural Science Foundation of Zhejiang Province (LY15C020001) and Si-Yuan Foundation.

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    Authors and Affiliations

    1. Research Centre of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences, Zhejiang University, Hangzhou, 310058, People’s Republic of China

      Jun Xiang, Zhe Wang, Xia Li, Jianguo Sun & Feiyan Liu

    2. Joint Centre of Zhejiang University and the Chinese University of Hong Kong on Natural Products and Toxicology Research, Zhejiang University, Hangzhou, People’s Republic of China

      Jun Xiang, Zhe Wang, Xia Li, Jianguo Sun, Kwok-Pui Fung & Feiyan Liu

    3. Zhejiang University Hospital, Zhejiang University, Hangzhou, People’s Republic of China

      Qianqian Liu

    4. School of Biomedical Sciences (SBS), The Chinese University of Hong Kong, Shatin, Hong Kong SAR, People’s Republic of China

      Kwok-Pui Fung

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    1. Jun Xiang
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    Correspondence to Feiyan Liu.

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    All applicable international, national, and institutional guidelines for the care and use of animals were followed. This article does not contain any studies with human participants performed by any of the authors.

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    Jun Xiang, Zhe Wang and Qianqia Liu have contributed equally to this work.

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    Xiang, J., Wang, Z., Liu, Q. et al. DMFC (3,5-dimethyl-7H-furo[3,2-g]chromen-7-one) regulates Bim to trigger Bax and Bak activation to suppress drug-resistant human hepatoma. Apoptosis 22, 381–392 (2017). https://doi.org/10.1007/s10495-016-1331-5

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    • DOI: https://doi.org/10.1007/s10495-016-1331-5

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