Exogenous cell-permeable C6 ceramide sensitizes multiple cancer cell lines to Doxorubicin-induced apoptosis by promoting AMPK activation and mTORC1 inhibition
Exogenous cell-permeable C6 ceramide sensitizes multiple cancer cell lines to Doxorubicin-induced apoptosis by promoting AMPK activation and mTORC1 inhibition
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DOI：
10.1038/onc.2010.379
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发表时间：
2010-12-01
期刊：
影响因子：
8
通讯作者：
Bi, Z-G
中科院分区：
文献类型：
--
作者：
Ji, C.;Yang, B.;Bi, Z-G
为了更好地治疗癌症，需要新的化疗增强策略。先前的研究表明，外源性细胞渗透性C6神经酰胺可能是化疗药物（如紫杉醇）对多种癌症的抗肿瘤作用的有用辅助。在这里，我们证明了外源性细胞渗透性C6神经酰胺在很大程度上使多个进展性癌细胞系对阿霉素诱导的细胞死亡和凋亡敏感。我们首次发现阿霉素以活性氧依赖的方式诱导amp活化蛋白激酶（AMPK）活化。AMPK的激活有助于阿霉素诱导的癌细胞死亡和凋亡。通过小干扰RNA敲低或药理学抑制剂抑制AMPK可减少阿霉素诱导的癌细胞凋亡，而AMPK激活剂AICAR可增强其凋亡。重要的是，我们发现C6神经酰胺在很大程度上增强了阿霉素诱导的AMPK活化，从而导致mTOR复合物1抑制和化学增敏。我们的数据表明，C6神经酰胺与传统化疗药物（如阿霉素）的联合治疗可能有潜力成为一种新的治疗多种癌症的干预手段。中华肿瘤杂志（2010）29 (2):557- 568；doi: 10.1038 / onc.2010.379;2010年8月30日在线发布
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. Oncogene (2010) 29, 6557-6568; doi:10.1038/onc.2010.379; published online 30 August 2010