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Caffeic acid phenethyl ester enhances TRAIL-mediated apoptosis via CHOP-induced death receptor 5 upregulation in hepatocarcinoma Hep3B cells

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Abstract

Caffeic acid phenethyl ester (CAPE) exhibits various pharmaceutical properties, including anti-bacterial, anti-inflammatory, anti-viral, anti-cancer, and anti-oxidative activity. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been a promising anti-cancer agent that preferentially induces cancer cell apoptosis with negligible cytotoxicity toward normal cells. Therefore, the present study investigated whether CAPE promotes TRAIL-mediated cytotoxicity in hepatocarcinoma Hep3B cells. The present study demonstrated that CAPE sensitized TRAIL-mediated cell death in Hep3B carcinoma cells. The percentages of the apoptotic cells and annexin-V+ cells significantly increased in combined treatment with CAPE and TRAIL (CAPE/TRAIL). Treatment with pancaspase inhibitor, z-VAD-fmk, attenuated CAPE/TRAIL-induced apoptosis, suggesting that the combined treatment triggers caspase-dependent apoptosis. Additionally, we found that CAPE stimulated the expression of death receptor 5 (DR5) and treatment with DR5/Fc chimera protein significantly blocked CAPE/TRAIL-induced apoptosis, which indicates that CAPE/TRAIL stimulated apoptosis through the binding of TRAIL to DR5. Moreover, expression of transcription factor C/EBP homologous protein (CHOP) markedly increased in response to CAPE and transient knockdown of CHOP abolished CAPE/TRAIL-mediated apoptosis. These results suggest that CHOP is a key regulator in CAPE/TRAIL-mediated apoptosis. Taken together, the present study found that CAPE significantly enhanced TRAIL-mediated apoptosis in Hep3B carcinoma cells and suggested that CAPE has promising potential in chemoprevention of hepatocellular carcinomas.

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Acknowledgments

This study was supported by Basic Science Research Program (2015R1D1A1A01060538) through the National Research Foundation of Korea (NRF) funded from the Ministry of Education, Science and Technology of Korea.

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Authors and Affiliations

  1. Department of Marine Life Sciences, Jeju National University, Jeju, 63243, Republic of Korea

    Matharage Gayani Dilshara, Rajapaksha Gedara Prasad Tharanga Jayasooriya, Sang Rul Park & Gi-Young Kim

  2. Department of Biochemistry, College of Oriental Medicine, Dong-Eui University, Busan, 47340, Republic of Korea

    Yung-Hyun Choi

  3. Department of Microbiology, College of Medicine, Inje University, Busan, 47392, Republic of Korea

    Il-Whan Choi

Authors
  1. Matharage Gayani Dilshara
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  2. Rajapaksha Gedara Prasad Tharanga Jayasooriya
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  3. Sang Rul Park
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  4. Yung-Hyun Choi
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  5. Il-Whan Choi
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  6. Gi-Young Kim
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Correspondence to Gi-Young Kim.

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Dilshara, M.G., Jayasooriya, R.G.P.T., Park, S.R. et al. Caffeic acid phenethyl ester enhances TRAIL-mediated apoptosis via CHOP-induced death receptor 5 upregulation in hepatocarcinoma Hep3B cells. Mol Cell Biochem 418, 13–20 (2016). https://doi.org/10.1007/s11010-016-2726-x

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  • DOI: https://doi.org/10.1007/s11010-016-2726-x

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