Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR
Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR
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DOI：
10.1073/pnas.171076798
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发表时间：
2001-08-28
影响因子：
11.1
通讯作者：
Sawyers, CL
中科院分区：
文献类型：
--
作者：
Neshat, MS;Mellinghoff, IK;Sawyers, CL
最近的证据将FRAP/mTOR激酶置于磷脂酰肌醇3-激酶/Akt信号传导途径的下游，由于PTEN肿瘤抑制基因的丢失，该途径在多种癌症中上调。我们进行了生物学和生物化学研究，以确定是否PTEN缺陷的癌细胞是敏感的FRAP/mTOR的药理学抑制使用雷帕霉素衍生物CCl-779。在体外和体内研究的同基因的PTEN+/+和PTEN-/-小鼠细胞以及人类癌细胞与定义的PTEN状态显示，PTEN空细胞的生长被阻断优先通过药理FRAP/mTOR抑制。由PTEN+/+细胞中Akt的组成性激活引起的增强的肿瘤生长也被CCl-779处理逆转，表明FRAP/mTOR在肿瘤发生中的Akt下游起作用。PTEN的缺失与S6激酶活性增加和核糖体S6蛋白磷酸化相关，为这些细胞中FRAP/mTOR通路的激活提供了证据。对CCl-779的不同敏感性不能用FRAP/mTOR通路的生物化学阻断的差异来解释，因为S6磷酸化在敏感和耐药细胞系中被抑制。这些结果提供了在PTEN缺失的人类癌症中测试FRAP/mTOR抑制剂的基本原理。
Recent evidence places the FRAP/mTOR kinase downstream of the phosphatidyl inositol 3-kinase/Akt-signaling pathway, which is up-regulated in multiple cancers because of loss of the PTEN tumor suppressor gene. We performed biological and biochemical studies to determine whether PTEN-deficient cancer cells are sensitive to pharmacologic inhibition of FRAP/mTOR by using the rapamycin derivative CCl-779. In vitro and in vivo studies of isogenic PTEN+/+ and PTEN-/- mouse cells as well as human cancer cells with defined PTEN status showed that the growth of PTEN null cells was blocked preferentially by pharmacologic FRAP/mTOR inhibition. Enhanced tumor growth caused by constitutive activation of Akt in PTEN+/+ cells also was reversed by CCl-779 treatment, indicating that FRAP/mTOR functions downstream of Akt in tumorigenesis. Loss of PTEN correlated with increased S6 kinase activity and phosphorylation of ribosomal S6 protein, providing evidence for activation of the FRAP/mTOR pathway in these cells. Differential sensitivity to CCl-779 was not explained by differences in biochemical blockade of the FRAP/mTOR pathway, because S6 phosphorylation was inhibited in sensitive and resistant cell lines. These results provide rationale for testing FRAP/mTOR inhibitors in PTEN null human cancers.