Tripchlorolide induces autophagy in lung cancer cells by inhibiting the PI3K/AKT/mTOR pathway and improves cisplatin sensitivity in A549/DDP cells.
Tripchlorolide induces autophagy in lung cancer cells by inhibiting the PI3K/AKT/mTOR pathway and improves cisplatin sensitivity in A549/DDP cells.
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三氯内酯通过抑制 PI3K/AKT/mTOR 通路诱导肺癌细胞自噬并提高 A549/DDP 细胞对顺铂的敏感性
DOI：
10.18632/oncotarget.19201
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发表时间：
2017-09-08
期刊：
影响因子：
--
通讯作者：
Lin TY
中科院分区：
文献类型：
--
作者：
Chen LM;Song TJ;Xiao JH;Huang ZH;Li Y;Lin TY
三氯内酯（T4）主要通过激活自噬途径诱导A549肺癌细胞死亡。然而，其潜在机制尚不清楚。本研究表明，与单独T4治疗相比，wortmannin（一种磷脂酰肌醇3-激酶抑制剂）、perifosine（一种AKT抑制剂）或rapamycin（一种mTOR抑制剂）预处理联合随后的T4治疗显著降低了A549和A549/DDP肺癌细胞的细胞活力。我们发现两种治疗方案均可显著降低P13K和AKT的活性。在A549和A549/DDP细胞中，LC3II的表达与T4浓度的升高同步升高，并被AKT过表达抑制。wortmannin、perifosine或雷帕霉素+ T4处理对PI3-K、PI3-P、AKT、TSC2、mTOR、p70S6K和4E-BP1的表达水平影响较小，但其磷酸化产物在A549肺癌细胞中受影响较大，在A549/DDP肺癌细胞中受影响较小。这些结果表明，T4通过抑制PI3K/AKT/mTOR信号通路诱导肺癌细胞自噬。我们进一步发现T4降低了MDR1的表达，提高了A549/DDP细胞的顺铂敏感性。总之，这些结果对未来的肿瘤治疗具有重要意义。
Tripchlorolide (T4) has been shown to induce A549 lung cancer cell death predominantly by activating an autophagy pathway. However, the underlying mechanism remains unclear. Herein, we demonstrated that compared with T4 treatment alone, pretreatment with wortmannin (an inhibitor of phosphatidylinositol 3-kinase), perifosine (an inhibitor of AKT) or rapamycin (an inhibitor of mTOR) combined with a subsequent T4 treatment significantly impaired the cell viability of A549 and A549/DDP lung cancer cells. We found that either treatment scheme markedly reduced the activity of P13K and AKT. Expression of LC3II increased in parallel to the increase of the T4 concentration in both A549 and A549/DDP cells and was repressed by overexpression of AKT. The expression levels of PI3-K, PI3-P, AKT, TSC2, mTOR, p70S6K and 4E-BP1 were minimally affected by the wortmannin, perifosine, or rapamycin plus T4 treatments, but their phosphorylated products were greatly affected in A549 lung cancer cells and slightly affected in A549/DDP lung cancer cells. These results indicate that T4 induces autophagy in lung cancer cells by inhibiting the PI3K/AKT/mTOR signaling pathway. We further found that T4 decreased expression of MDR1 and improved cisplatin sensitivity of A549/DDP cells. Altogether, these results have meaningful implications for tumor therapy in the future.
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DOI：
10.2147/dddt.s69690
发表时间：
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期刊：
Drug design, development and therapy
影响因子：
--
作者：
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