Alantolactone induces apoptosis and improves chemosensitivity of pancreatic cancer cells by impairment of autophagy-lysosome pathway via targeting TFEB
Alantolactone induces apoptosis and improves chemosensitivity of pancreatic cancer cells by impairment of autophagy-lysosome pathway via targeting TFEB
复制标题
Alantolactone 通过靶向 TFEB 损害自噬-溶酶体途径诱导细胞凋亡并提高胰腺癌细胞的化疗敏感性
DOI：
10.1016/j.taap.2018.08.003
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发表时间：
2018-10-01
影响因子：
3.8
通讯作者：
Qin, Renyi
中科院分区：
文献类型：
--
作者：
He, Ruizhi;Shi, Xiuhui;Qin, Renyi
溶酶体作为自噬过程的中央调节器出现，自噬过程在肿瘤生长和化学抗性中起关键作用。土木香内酯是由旋覆花产生的天然化合物，已被证明在许多癌症类型中诱导细胞凋亡。然而，土木香内酯调节细胞凋亡的机制仍然知之甚少。在这项工作中，我们观察到，土木香内酯引起的自噬体的积累，由于受损的自噬降解和显着抑制CTSB/CTSD蛋白的活性和表达，当耗尽引起溶酶体功能障碍。此外，我们还发现土木香内酯在体内外均能抑制胰腺癌细胞的增殖，并能增强胰腺癌细胞对奥沙利铂的化疗敏感性。此外，TFEB水平的降低是由土木香内酯引起的细胞凋亡和细胞死亡的关键事件。我们的数据表明，alantolactone，损害自噬降解，是一种药理学抑制剂的胰腺癌细胞中的自噬，并显着提高胰腺癌细胞对奥沙利铂的化疗敏感性。
The lysosome is emerging as a central regulator of the autophagic process, which plays a critical role in tumor growth and chemoresistance. Alantolactone, which is a natural compound produced by Inula heleniwn, has been shown to induce apoptosis in numerous cancer types. However, the mechanism by which alantolactone regulates apoptosis is still poorly understood. In this work, we observed that alantolactone caused the accumulation of autophagosomes due to impaired autophagic degradation and substantially inhibited the activity and expression of CTSB/CTSD proteins that when depleted caused lysosomal dysfunction. Furthermore, we found that alantolactone inhibited the proliferation of pancreatic cancer cells in vitro and in vivo and enhanced the chemosensitivity of pancreatic cancer cells to oxaliplatin. In addition, a reduction in TFEB levels was a critical event in the apoptosis and cell death caused by alantolactone. Our data demonstrated that alantolactone, which impaired autophagic degradation, was a pharmacological inhibitor of autophagy in pancreatic cancer cells and markedly enhanced the chemosensitivity of pancreatic cancer cells to oxaliplatin.