Reversal of the Apoptotic Resistance of Non-Small-Cell Lung Carcinoma towards TRAIL by Natural Product Toosendanin.
Reversal of the Apoptotic Resistance of Non-Small-Cell Lung Carcinoma towards TRAIL by Natural Product Toosendanin.
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天然产物川楝素逆转非小细胞肺癌对TRAIL的凋亡抗性
DOI：
10.1038/srep42748
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发表时间：
2017-02-17
影响因子：
4.6
通讯作者：
Yin W
中科院分区：
文献类型：
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作者：
Li X;You M;Liu YJ;Ma L;Jin PP;Zhou R;Zhang ZX;Hua B;Ji XJ;Cheng XY;Yin F;Chen Y;Yin W
肿瘤坏死因子相关凋亡诱导配体（tumor necrosis factor-related apoptosis-inducing ligand，TRAIL）通过与细胞膜上的死亡受体结合选择性地触发癌细胞死亡，但对正常细胞的副作用可以忽略不计。然而，一些非小细胞肺癌（NSCLC）患者在临床试验中表现出对TRAIL治疗的耐药性，其机制各不相同。在本研究中，我们首次描述了川楝素（TSN），一种用于治疗疼痛的中药三萜类衍生物，可以显着敏化人原代NSCLC细胞或NSCLC细胞系在体外和体内TRAIL介导的凋亡，而显示对人原代细胞或组织的低毒性。其凋亡机制涉及死亡受体5（DR 5）和CCAAT/增强子结合蛋白同源蛋白的上调，这与内质网应激反应有关，并进一步与活性氧的产生和Ca 2+的积累有关。令人惊讶的是，TSN还诱导NSCLC细胞中的自噬，其募集膜DR 5，并随后拮抗TSN的细胞毒性致敏作用。总之，TSN可用于致敏肿瘤，并且TRAIL和TSN的组合可能代表NSCLC治疗的有用策略;此外，自噬是TSN的重要耐药机制。
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively triggers cancer cell death via its association with death receptors on the cell membrane, but exerts negligible side effects on normal cells. However, some non-small-cell lung carcinoma (NSCLC) patients exhibited resistance to TRAIL treatment in clinical trials, and the mechanism varies. In this study, we described for the first time that toosendanin (TSN), a triterpenoid derivative used in Chinese medicine for pain management, could significantly sensitize human primary NSCLC cells or NSCLC cell lines to TRAIL-mediated apoptosis both in vitro and in vivo, while showing low toxicity against human primary cells or tissues. The underlying apoptotic mechanisms involved upregulation of death receptor 5 (DR5) and CCAAT/enhancer binding protein homologous protein, which is related to the endoplasmic reticulum stress response, and is further associated with reactive oxygen species generation and Ca 2+ accumulation. Surprisingly, TSN also induced autophagy in NSCLC cells, which recruited membrane DR5, and subsequently antagonized the apoptosis-sensitizing effect of TSN. Taken together, TSN can be used to sensitize tumors and the combination of TRAIL and TSN may represent a useful strategy for NSCLC therapy; moreover, autophagy serves as an important drug resistance mechanism for TSN.