Phosphatidylinositol ether lipid analogues induce AMP-activated protein kinase-dependent death in LKB1-mutant non-small cell lung cancer cells
Phosphatidylinositol ether lipid analogues induce AMP-activated protein kinase-dependent death in LKB1-mutant non-small cell lung cancer cells
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DOI：
10.1158/0008-5472.can-07-3091
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发表时间：
2008-01-15
期刊：
影响因子：
11.2
通讯作者：
Dennis, Phillip A.
中科院分区：
文献类型：
--
作者：
Memmott, Regan M.;Gills, Joell J.;Dennis, Phillip A.
肿瘤抑制基因LKB1的功能丧失发生在30%到50%的肺腺癌中。因为LKB1激活AMP激活的蛋白激酶(AMPK)，而AMPK可以负向调节mTOR，所以AMPK的激活可能是癌症治疗的理想选择。然而，目前还没有已知的化合物在体内独立于LKB1激活AMPK，并且激活AMPK在LKB1突变癌症中的作用尚不清楚。在这里，我们证明了基于脂质的Akt抑制剂，磷脂酰肌醇醚脂类似物(PIA)，独立于LKB1激活AMPK。PIAS在LKB1突变的非小细胞肺癌(NSCLC)细胞系中激活AMPK，其浓度依赖关系类似于抑制Akt所需的浓度。然而，AMPK的激活与Akt的抑制无关。AMPK激活是mTOR抑制的主要机制。为了评估另一种能够激活AMPK的激酶CaMKKβ是否有助于PIA诱导的AMPK激活，我们使用了CaMKK的抑制剂STO-609。STO-609抑制PIA诱导的LKB1突变型NSCLC细胞AMPK活化，并延迟野生型LKB1 NSCLC细胞AMPK激活。此外，在含有突变型CaMKKβ的NSCLC细胞中未观察到AMPK的激活，提示CaMKKβ参与了PIA诱导的细胞内AMPK的激活。AMPK激活促进了PIA诱导的细胞毒性，因为在AMPKα/-小鼠胚胎成纤维细胞或LKB1突变的NSCLC细胞中，PIA的细胞毒性较小。这一机制在体内也是相关的。用PIA治疗LKB1突变的NSCLC移植瘤可使肿瘤体积缩小约50%，并激活AMPK。这些研究表明，PIA概括了两个肿瘤抑制因子(PTEN和LKB1)的活性，它们聚集在mTOR上。此外，他们认为PIA可能在治疗LKB1突变的肺腺癌方面有用处。
Loss of function of the tumor suppressor LKB1 occurs in 30% to 50% of lung adenocarcinomas. Because LKB1 activates AMP-activated protein kinase (AMPK), which can negatively regulate mTOR, AMPK activation might be desirable for cancer therapy. However, no known compounds activate AMPK independently of LKB1 in vivo, and the usefulness of activating AMPK in LKB1-mutant cancers is unknown. Here, we show that lipid-based Akt inhibitors, phosphatidylinositol ether lipid analogues (PIA), activate AMPK independently of LKB1. PIAs activated AMPK in LKB1-mutant non-small cell lung cancer (NSCLC) cell lines with similar concentration dependence as that required to inhibit Akt. However, AMPK activation was independent of Akt inhibition. AMPK activation was a major mechanism of mTOR inhibition. To assess whether another kinase capable of activating AMPK, CaMKK beta, contributed to PIA-induced AMPK activation, we used an inhibitor of CaMKK, STO-609. STO-609 inhibited PIA-induced AMPK activation in LKB1-mutant NSCLC cells, and delayed AMPK activation in wild-type LKB1 NSCLC cells. In addition, AMPK activation was not observed in NSCLC cells with mutant CaMKK beta, suggesting that CaMKK beta contributes to PIA-induced AMPK activation in cells. AMPK activation promoted PIA-induced cytotoxicity because PIAs were less cytotoxic in AMPK alpha-/- murine embryonic fibroblasts or LKB1-mutant NSCLC cells transfected with mutant AMPK. This mechanism was also relevant in vivo. Treatment of LKB1-mutant NSCLC xenografts with PIA decreased tumor volume by similar to 50% and activated AMPK. These studies show that PIAs recapitulate the activity of two tumor suppressors (PTEN and LKB1) that converge on mTOR. Moreover, they suggest that PIAs might have utility in the treatment of LKB1-mutant lung adenocarcinomas.