Panner Amith, James C David, Berger Mitchel S, Pieper Russell O
Brain Tumor Research Center, Department of Neurological Surgery, University of California San Francisco, 94143-0875, USA.
Mol Cell Biol. 2005 Oct;25(20):8809-23. doi: 10.1128/MCB.25.20.8809-8823.2005.
The tumor-selective, proapoptotic, death receptor ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a mediator of antitumor drug activity and in itself is a promising agent for the treatment of human malignancies. Like many tumors, however, glioblastoma multiforme (GBM), the most fatal form of glioma, exhibits a range of TRAIL sensitivity, and only a small percentage of GBM tumors undergo TRAIL-induced apoptosis. We here show that TRAIL resistance in GBM is a consequence of overexpression of the short isoform of the caspase-8 inhibitor, c-FLICE inhibitory protein (FLIP(S)), and that FLIP(S) expression is in turn translationally enhanced by activation of the Akt-mammalian target of rapamycin (mTOR)-p70 S6 kinase 1 (S6K1) pathway. Conversely, pharmacologic or genetic inhibition of mTOR, or the mTOR target S6K1, suppresses polyribosomal accumulation of FLIP(S) mRNA, FLIP(S) protein expression, and TRAIL resistance. In archived material from 12 human GBM tumors, PTEN status was a predictor of activation of the Akt-mTOR-S6K1 pathway and of FLIP(S) levels, while in xenografted human GBM, activation status of the PTEN-Akt-mTOR pathway distinguished the tumors inherently sensitive to TRAIL from those which could be sensitized by the mTOR inhibitor rapamycin. These results define the mTOR pathway as a key limiter of tumor elimination by TRAIL-mediated mechanisms, provide a means by which the TRAIL-sensitive subset of GBM can be identified, and provide rationale for the combined use of TRAIL with mTOR inhibitors in the treatment of human cancers.
肿瘤选择性、促凋亡的死亡受体配体肿瘤坏死因子相关凋亡诱导配体（TRAIL）是抗肿瘤药物活性的介质，其本身就是治疗人类恶性肿瘤的一种有前景的药物。然而，与许多肿瘤一样，多形性胶质母细胞瘤（GBM），即最致命的胶质瘤形式，表现出一系列TRAIL敏感性，只有一小部分GBM肿瘤会发生TRAIL诱导的凋亡。我们在此表明，GBM中TRAIL耐药是半胱天冬酶8抑制剂c-FLICE抑制蛋白（FLIP(S)）短异构体过表达的结果，而FLIP(S)的表达又通过Akt-雷帕霉素哺乳动物靶标（mTOR）-p70 S6激酶1（S6K1）途径的激活而在翻译水平上增强。相反，对mTOR或mTOR靶标S6K1的药理或基因抑制可抑制FLIP(S) mRNA的多核糖体积累、FLIP(S)蛋白表达和TRAIL耐药性。在来自12例人类GBM肿瘤的存档材料中，PTEN状态是Akt-mTOR-S6K1途径激活和FLIP(S)水平的预测指标，而在异种移植的人类GBM中，PTEN-Akt-mTOR途径的激活状态区分了对TRAIL固有敏感的肿瘤和可被mTOR抑制剂雷帕霉素致敏的肿瘤。这些结果将mTOR途径定义为TRAIL介导机制消除肿瘤的关键限制因素，提供了一种识别GBM中TRAIL敏感亚群的方法，并为TRAIL与mTOR抑制剂联合用于治疗人类癌症提供了理论依据。
