Loss of tuberous sclerosis complex-2 function and activation of mammalian target of rapamycin signaling in endometrial carcinoma
Loss of tuberous sclerosis complex-2 function and activation of mammalian target of rapamycin signaling in endometrial carcinoma
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DOI：
10.1158/1078-0432.ccr-07-0321
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发表时间：
2008-05-01
影响因子：
11.5
通讯作者：
Walker, Cheryl Lyn
中科院分区：
文献类型：
--
作者：
Lu, Karen H.;Wu, Weiguo;Walker, Cheryl Lyn
目的：十号染色体上缺失的磷酸酶和紧张素同源物（PTEN）在子宫内膜癌中的作用与磷脂酰肌醇3-激酶信号通路和哺乳动物雷帕霉素靶蛋白（mTOR）的激活有关。了解mTOR的参与程度和激活机制是很重要的，因为mTOR抑制剂目前正在子宫内膜癌的临床试验中进行评估。尽管结节性硬化症复合体2 （TSC2）是mTOR激活的“看门人”，但对于TSC2肿瘤抑制因子或调节TSC2的信号通路（如LKB1/AMP活化蛋白激酶）在子宫内膜癌发展中的缺陷知之甚少。实验设计：我们确定了子宫内膜癌（原发肿瘤和细胞系）中mTOR激活的频率，并研究了PTEN、LKB1和TSC2缺陷作为mTOR激活的潜在原因，并确定了雷帕霉素逆转子宫内膜癌细胞中这些信号缺陷的能力。结果：mTOR的激活在子宫内膜癌和细胞系中是一致的特征。除PTEN外，TSC2和LKB1的表达缺失也发生在相当一部分原发肿瘤中（分别为13%和21%）。在保留TSC2表达的肿瘤中，高频率地观察到tuberin在S939位点的磷酸化，这表明TSC2对mTOR的抑制通过AKT磷酸化该肿瘤抑制因子而得到缓解。在TSC2功能失活的PTEN-null和LKB1-null子宫内膜癌细胞系中，磷脂酰肌醇3-激酶（PI3K）抑制剂wortmannin和LY294002能够抑制AKT和mTOR信号传导，逆转TSC2磷酸化。相比之下，虽然雷帕霉素抑制mTOR信号传导，但它并没有减轻TSC2在S939位点的磷酸化。结论：TSC2通过表达缺失或磷酸化失活在子宫内膜癌中经常发生，从而激活mTOR信号。高频mTOR激活支持mTOR作为子宫内膜癌的合理治疗靶点。然而，尽管雷帕霉素及其类似物可能有效抑制mTOR活性，但这些药物并不能逆转这些肿瘤中发生的TSC2功能失活。
Purpose: The involvement of phosphatase and tensin homologue deleted on chromosome ten (PTEN) in endometrial carcinoma has implicated phosphatidylinositol 3-kinase Signaling and mammalian target of rapamycin (mTOR) activation in this disease. Understanding the extent of mTOR involvement and the mechanism responsible for activation is important, as mTOR inhibitors are currently being evaluated in clinical trials for endometrial carcinoma. Although tuberous sclerosis complex 2 (TSC2) is the "gatekeeper" for mTOR activation, little is known about defects in the TSC2 tumor suppressor or signaling pathways that regulate TSC2, such as LKB1/AMP activated protein kinase, in the development of endometrial carcinoma.Experimental Design:We determined the frequency of mTOR activation in endometrial carcinoma (primary tumors and cell lines) and investigated PTEN, LKB1, and TSC2 defects as underlying cause(s) of mTOR activation, and determined the ability of rapamycin to reverse these signaling defects in endometrial carcinoma cells.Results: Activation of mTOR was a consistent feature in endometrial carcinomas and cell lines. In addition to PTEN, loss of TSC2 and LKB1 expression occurred in a significant fraction of primary tumors (13% and 21%, respectively). In tumors that retained TSC2 expression, phosphorylation of tuberin at S939 was observed with a high frequency, indicating that mTOR repression by TSC2 had been relieved via AKT phosphorylation of this tumor suppressor. In PTEN-null and LKB1-null endometrial carcinoma cell lines with functional inactivation of TSC2, phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin and LY294002 were able to inhibit AKT and mTOR signaling and reverse TSC2 phosphorylation. In contrast, although rapamycin inhibited mTOR signaling, it did not relieve phosphorylation of TSC2 at S939.Conclusions: Inactivation of TSC2 via loss of expression or phosphorylation occurred frequently in endometrial carcinoma to activate mTOR signaling. High-frequency mTOR activation supports mTOR as a rational therapeutic target for endometrial carcinoma. However, whereas rapamycin and its analogues may be efficacious at inhibiting mTOR activity, these drugs do not reverse the functional inactivation of TSC2 that occurs in these tumors.