Dual blocking of mTor and PI3K elicits a prodifferentiation effect on glioblastoma stem-like cells
Dual blocking of mTor and PI3K elicits a prodifferentiation effect on glioblastoma stem-like cells
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DOI：
10.1093/neuonc/noq103
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发表时间：
2010-12-01
期刊：
影响因子：
15.9
通讯作者：
Kitanaka, Chifumi
中科院分区：
文献类型：
--
作者：
Sunayama, Jun;Sato, Atsushi;Kitanaka, Chifumi
胶质母细胞瘤是最难治的脑肿瘤，具有高度致命性。最近的研究表明，癌症干细胞样细胞（CSLCs）有能力重新填充肿瘤并介导放射性和化学抗性，这意味着未来的治疗可能需要从消除快速分裂但分化的肿瘤细胞转向特异性靶向少数肿瘤细胞。然而，胶质母细胞瘤CSLCs维持其未成熟干细胞样状态或致力于分化的机制知之甚少。在这里，我们表明，失活的哺乳动物靶雷帕霉素（mTor）的mTor抑制剂雷帕霉素或敲低mTor减少球体的形成和表达的神经干细胞（NSC）/祖细胞标志物的CSLC的A172胶质母细胞瘤细胞系。有趣的是，雷帕霉素和磷脂酰肌醇3-激酶（PI 3 K）抑制剂LY 294002的联合治疗不仅比单药治疗更有效地降低了NSC/祖细胞标志物的表达，而且还增加了β III-微管蛋白（神经元分化标志物）的表达。与这些结果一致，双重PI 3 K/mTor抑制剂NVP-BEZ 235引起对A172 CSLC的促分化作用。此外，当皮下或颅内移植时，通过用NVP-BEZ 235预处理诱导经历分化的A172 CSLC表现出其致瘤性的显著降低。重要的是，当使用患者来源的胶质母细胞瘤CSLC时获得了类似的结果。这些发现表明PI 3 K/mTor信号通路对于维持胶质母细胞瘤CSLC特性至关重要，靶向CSLC的mTor和PI 3 K可能是胶质母细胞瘤的有效治疗策略。
Glioblastoma, the most intractable cerebral tumor, is highly lethal. Recent studies suggest that cancer stem-like cells (CSLCs) have the capacity to repopulate tumors and mediate radio- and chemoresistance, implying that future therapies may need to turn from the elimination of rapidly dividing, but differentiated, tumor cells to specifically targeting the minority of tumor cells that repopulate the tumor. However, the mechanism by which glioblastoma CSLCs maintain their immature stem-like state or, alternatively, become committed to differentiation is poorly understood. Here, we show that the inactivation of mammalian target of rapamycin (mTor) by the mTor inhibitor rapamycin or knockdown of mTor reduced sphere formation and the expression of neural stem cell (NSC)/progenitor markers in CSLCs of the A172 glioblastoma cell line. Interestingly, combination treatment with rapamycin and LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor, not only reduced the expression of NSC/progenitor markers more efficiently than single-agent treatment, but also increased the expression of beta III-tubulin, a neuronal differentiation marker. Consistent with these results, a dual PI3K/mTor inhibitor, NVP-BEZ235, elicited a prodifferentiation effect on A172 CSLCs. Moreover, A172 CSLCs, which were induced to undergo differentiation by pretreatment with NVP-BEZ235, exhibited a significant decrease in their tumorigenicity when transplanted either subcutaneously or intracranially. Importantly, similar results were obtained when patient-derived glioblastoma CSLCs were used. These findings suggest that the PI3K/mTor signaling pathway is critical for the maintenance of glioblastoma CSLC properties, and targeting both mTor and PI3K of CSLCs may be an effective therapeutic strategy in glioblastoma.