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Exogenous cell-permeable C6 ceramide sensitizes multiple cancer cell lines to Doxorubicin-induced apoptosis by promoting AMPK activation and mTORC1 inhibition

Oncogene volume 29, pages 6557–6568 (2010)Cite this article

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Abstract

New chemotherapy-enhancing strategies are needed for better cancer therapy. Previous studies suggest that exogenous cell-permeable C6 ceramide may be a useful adjunct to the anti-tumor effects of chemotherapeutic agents (such as Taxol) against multiple cancers. Here we demonstrate that exogenous cell-permeable C6 ceramide largely sensitizes multiple progressive cancer cell lines to Doxorubicin-induced cell death and apoptosis. We found for the first time that Doxorubicin induces AMP-activated protein kinase (AMPK) activation in a reactive oxygen species-dependent manner. Activation of AMPK contributes to Doxorubicin-induced cancer cell death and apoptosis. Inhibition of AMPK by small interfering RNA knockdown or a pharmacological inhibitor reduces Doxorubicin-induced cancer cell apoptosis, whereas AMPK activator AICAR enhances it. Importantly, we found that C6 ceramide largely enhances Doxorubicin-induced activation of AMPK, which leads to mTOR complex 1 inhibition and chemo-sensitization. Our data suggest that the combination of C6 ceramide with traditional chemotherapy drugs such as Doxorubicin may have the potential to be used as a new therapeutic intervention against multiple cancers.

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Acknowledgements

This research was supported in part by grants from the National Natural Science Foundation of China (30271195 and 30671894).

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Author notes

  1. C Ji, B Yang and Y-L Yang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China

    C Ji

  2. Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China

    B Yang

  3. Department of Otolaryngology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China

    Y-L Yang

  4. Clinical Experiment Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China

    S-H He

  5. Department of Human Anatomy, Nanjing Medical University, Nanjing, Jiangsu, China

    D-S Miao

  6. Department of Dermatology, The First Affiliated Hospital of Kunming Medical University, Yunnan Provincial Institute of Dermatology, Kunming, Yunnan, China

    L He

  7. Department of Dermatology, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, Jiangsu, China

    Z-G Bi

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  1. C Ji
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Correspondence to C Ji, L He or Z-G Bi.

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Ji, C., Yang, B., Yang, YL. et al. Exogenous cell-permeable C6 ceramide sensitizes multiple cancer cell lines to Doxorubicin-induced apoptosis by promoting AMPK activation and mTORC1 inhibition. Oncogene 29, 6557–6568 (2010). https://doi.org/10.1038/onc.2010.379

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