Rapamycin requires AMPK activity and p27 expression for promoting autophagy-dependent Tsc2-null cell survival
Rapamycin requires AMPK activity and p27 expression for promoting autophagy-dependent Tsc2-null cell survival
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DOI：
10.1016/j.bbamcr.2016.03.009
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发表时间：
2016-06-01
影响因子：
5.1
通讯作者：
Castro, Ariel F.
中科院分区：
文献类型：
--
作者：
Campos, Tania;Ziehe, Javiera;Castro, Ariel F.
结节性硬化症（TSC）是由TSC1或TSC2基因失活引起的疾病，其特征是在几个器官中出现良性肿瘤。由于TSC肿瘤发生与mTORC1的过度激活相关，目前的治疗方法主要是用雷帕霉素或其类似物抑制mTORC1。雷帕霉素诱导肿瘤缩小已有报道，但肿瘤复发发生在停药雷帕霉素。在雷帕霉素治疗期间，自噬与TSC肿瘤的发展和肿瘤细胞存活有关，mTORC1和AMPK分别直接抑制和激活自噬。AMPK在TSC细胞和肿瘤中被过度激活，并驱动细胞质隔离细胞周期抑制剂p27KIP （p27）。AMPK和p27是否参与雷帕霉素诱导的TSC细胞自噬和存活尚不清楚。在这里，我们发现通过化合物C或shrna介导的LKB1缺失抑制AMPK可降低雷帕霉素在tsc2缺失细胞中自噬的激活。同样，shrna介导的p27缺失抑制雷帕霉素诱导的自噬。p27位于AMPK下游，在tsc2缺失的细胞中激活自噬，一个优先定位于细胞质的p27突变体在p27缺失和lkb1缺失的细胞中恢复了雷帕霉素对自噬的影响，但一个核p27突变体没有活性。最后，我们发现p27依赖性的自噬激活参与了雷帕霉素治疗下tsc2缺失细胞的存活。这些结果表明AMPK/p27轴促进了一种生存机制，可以部分解释雷帕霉素治疗的TSC肿瘤复发，为设计更有效的TSC患者治疗方法提供了新的途径。(C) 2016 Elsevier B.V.版权所有
Tuberous sclerosis complex (TSC) disease results from inactivation of the TSC1 or TSC2 gene, and is characterized by benign tumors in several organs. Because TSC tumorigenesis correlates with hyperactivation of mTORC1, current therapies focus on mTORC1 inhibition with rapamycin or its analogs. Rapamycin-induced tumor shrinkage has been reported, but tumor recurrence occurs on withdrawal from rapamycin. Autophagy has been associated with development of TSC tumors and with tumor cell survival during rapamycin treatment mTORC1 and AMPK directly inhibit and activate autophagy, respectively. AMPK is hyperactivated in TSC cells and tumors, and drives cytoplasmic sequestration of the cell-cycle inhibitor p27KIP (p27). Whether AMPK and p27 are involved in rapamycin-induced autophagy and survival of TSC cells remain unexplored. Here, we show that inhibition of AMPK by compound C or by shRNA-mediated depletion of LKB1 reduces activation of autophagy by rapamycin in Tsc2-null cells. Similarly, shRNA-mediated depletion of p27 inhibited rapamycin-induced autophagy. In support of p27 lying downstream of AMPK on the activation of autophagy in Tsc2-null cells, a p27 mutant that preferentially localizes in the cytosol recovered the effect of rapamycin on autophagy in both p27- and LKB1-depleted cells, but a nuclear p27 mutant was inactive. Finally, we show that p27-dependent activation of autophagy is involved in Tsc2-null cell survival under rapamycin treatment. These results indicate that an AMPK/p27 axis is promoting a survival mechanism that could explain in part the relapse of TSC tumors treated with rapamycin, exposing new avenues for designing more efficient treatments for TSC patients. (C) 2016 Elsevier B.V. All rights reserved.