FoxO3a Functions as a Key Integrator of Cellular Signals That Control Glioblastoma Stem-like Cell Differentiation and Tumorigenicity
FoxO3a Functions as a Key Integrator of Cellular Signals That Control Glioblastoma Stem-like Cell Differentiation and Tumorigenicity
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DOI：
10.1002/stem.696
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发表时间：
2011-09-01
期刊：
影响因子：
5.2
通讯作者：
Kitanaka, Chifumi
中科院分区：
文献类型：
--
作者：
Sunayama, Jun;Sato, Atsushi;Kitanaka, Chifumi
胶质母细胞瘤是最具侵袭性的人类癌症类型之一，即使在多模式干预后也会发生恒定和致命的复发，癌症干细胞样细胞（CSLC）现在对此负责。我们最近的研究结果表明，磷酸肌醇-3-激酶/Akt/哺乳动物雷帕霉素靶蛋白（mTOR）和丝裂原活化蛋白/细胞外信号调节激酶激酶（MEK）/细胞外信号调节激酶（ERK）途径的联合抑制有效地促进胶质母细胞瘤CSLC的分化，从而抑制其致瘤性。然而，这两种信号通路协调调节分化和致瘤性的机制仍然未知。在这里，我们确定了FoxO 3a，Akt和ERK的共同磷酸化靶点，作为整合来自这些途径的信号的关键转录因子。两种途径的联合阻断引起FoxO 3a的核积累和激活比单独阻断更有效，并以FoxO 3a表达依赖的方式促进胶质母细胞瘤CSLCs的分化。此外，缺乏Akt和ERK磷酸化位点的组成型活性FoxO 3a突变体的表达足以诱导胶质母细胞瘤CSLC的分化并降低其致瘤性。这些发现表明FoxO 3a可能通过PI 3 K/Akt/mTOR和MEK/ERK信号通路在控制胶质母细胞瘤CSLC的分化和致瘤性中发挥关键作用，并且还意味着开发靶向有效FoxO 3a活化的方法可能是胶质母细胞瘤治疗的潜在方法。干细胞2011;29：1327-1337
Glioblastoma is one of the most aggressive types of human cancer, with invariable and fatal recurrence even after multimodal intervention, for which cancer stem-like cells (CSLCs) are now being held responsible. Our recent findings indicated that combinational inhibition of phosphoinositide-3-kinase/Akt/mammalian target of rapamycin (mTOR) and mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathways effectively promotes the commitment of glioblastoma CSLCs to differentiation and thereby suppresses their tumorigenicity. However, the mechanism by which these two signaling pathways are coordinated to regulate differentiation and tumorigenicity remains unknown. Here, we identified FoxO3a, a common phosphorylation target for Akt and ERK, as a key transcription factor that integrates the signals from these path-ways. Combinational blockade of both the pathways caused nuclear accumulation and activation of FoxO3a more efficiently than blockade of either alone, and promoted differentiation of glioblastoma CSLCs in a FoxO3a expression-dependent manner. Furthermore, the expression of a constitutively active FoxO3a mutant lacking phosphorylation sites for both Akt and ERK was sufficient to induce differentiation and reduce tumorigenicity of glioblastoma CSLCs. These findings suggest that FoxO3a may play a pivotal role in the control of differentiation and tumorigenicity of glioblastoma CSLCs by the PI3K/Akt/mTOR and MEK/ERK signaling pathways, and also imply that developing methods targeting effective FoxO3a activation could be a potential approach to the treatment of glioblastoma. STEM CELLS 2011;29:1327-1337