Suppression of mTOR pathway and induction of autophagy-dependent cell death by cabergoline.
Suppression of mTOR pathway and induction of autophagy-dependent cell death by cabergoline.
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卡麦角林抑制 mTOR 通路并诱导自噬依赖性细胞死亡
DOI：
10.18632/oncotarget.5744
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发表时间：
2015-11-17
期刊：
影响因子：
--
通讯作者：
Wu ZB
中科院分区：
文献类型：
--
作者：
Lin SJ;Leng ZG;Guo YH;Cai L;Cai Y;Li N;Shang HB;Le WD;Zhao WG;Wu ZB
卡麦角林（CAB）是治疗催乳素瘤的一线药物，可有效抑制催乳素分泌过多，缩小肿瘤大小，恢复性腺功能。然而，CAB介导的肿瘤缩小的机制在很大程度上是未知的。在这里，我们报告了一种新的细胞毒性机制CAB。CAB通过抑制mTOR通路诱导大鼠垂体瘤MMQ和GH 3细胞早期形成自噬体，导致LC 3-I向LC 3-II的转化率升高，GFP-LC 3聚集，自噬体形成增加。有趣的是，CAB处理增强了溶酶体酸化，并导致自体溶酶体内的蛋白水解降解受损。这阻断了自噬通量，导致p62聚集和未消化的自溶体的积累。ATG 7、ATG 5或Becn 1的敲低可显著挽救CAB介导的MMQ细胞的细胞死亡（p < 0.05）。CAB诱导的自噬和阻断自噬流参与体内抗肿瘤作用。总之，我们的研究提供的证据表明，CAB伴随诱导自噬和抑制自噬通量，导致自噬依赖性细胞死亡。这些发现阐明了CAB作用的新机制。
Cabergoline (CAB), the first-line drug for treatment of prolactinomas, is effective in suppressing prolactin hypersecretion, reducing tumor size, and restoring gonadal function. However, mechanisms for CAB-mediated tumor shrinkage are largely unknown. Here we report a novel cytotoxic mechanism for CAB. CAB induced formation of autophagosome in rat pituitary tumor MMQ and GH3 cells at the early stage through inhibiting mTOR pathway, resulting in higher conversion rates of LC3-I to LC3-II, GFP-LC3 aggregation, and increased autophagosome formation. Interestingly, CAB treatment augmented lysosome acidification and resulted in impaired proteolytic degradation within autolysosomes. This blocked the autophagic flux, leading to the accumulation of p62 aggregation and undigested autolysosomes. Knockdown of ATG7, ATG5, or Becn1, could significantly rescue the CAB-mediated cell death of MMQ cells (p < 0.05). CAB-induced autophagy and blockade of autophagy flux participated in antitumoral action in vivo. In conclusion, our study provides evidence that CAB concomitantly induces autophagy and inhibits the autophagic flux, leading to autophagy-dependent cell death. These findings elucidate novel mechanisms for CAB action.