Crosstalk Between the PI3K/mTOR and MEK/ERK Pathways Involved in the Maintenance of Self-Renewal and Tumorigenicity of Glioblastoma Stem-Like Cells
Crosstalk Between the PI3K/mTOR and MEK/ERK Pathways Involved in the Maintenance of Self-Renewal and Tumorigenicity of Glioblastoma Stem-Like Cells
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DOI：
10.1002/stem.521
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发表时间：
2010-11-01
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;Matsuda, Ken-Ichiro;Kitanaka, Chifumi
协调癌症干细胞样细胞（CSLC）（包括胶质母细胞瘤）生物学的分子信号通路仍有待阐明。在这项研究中，我们研究了MEK/细胞外信号调节激酶（ERK）通路在控制胶质母细胞瘤CSLC的自我更新和致瘤性中的作用，特别是与PI 3 K/mTOR（哺乳动物雷帕霉素靶蛋白）通路的关系。使用药理学抑制剂或siRNA单独靶向灭活MEK导致细胞系和患者来源的胶质母细胞瘤CSLC的球体形成减少，伴随着它们分化为神经元和神经胶质谱系。有趣的是，MEK失活的这种作用在NVP-BEZ 235（PI 3 K和mTOR的双重抑制剂）的存在下明显增强。作为这种观察到的协同作用的一个潜在解释，我们发现MEK/ERK或PI 3 K/mTOR通路的失活触发了另一个的激活，这表明这两个通路之间可能存在相互抑制的串扰。值得注意的是，任一途径的失活导致p70 S6 K的活化减少，并且siRNA介导的p70 S6 K敲低导致两种途径的活化，其不再保持交叉抑制关系。最后，在胶质母细胞瘤CSLCs中联合阻断这两种途径抑制其致瘤性，无论是皮下移植还是颅内移植，都比单独阻断更有效。我们的研究结果表明，有p70 S6 K介导的，交叉抑制调节之间的MEK/ERK和PI 3 K/mTOR途径，其中每一个有助于维持自我更新和胶质母细胞瘤CSLC的致瘤能力。因此，这些途径的组合中断将是一个合理的和有效的策略，在胶质母细胞瘤的治疗。干细胞2010;28：1930-1939
The molecular signaling pathways orchestrating the biology of cancer stem-like cells (CSLCs), including glioblastoma, remain to be elucidated. We investigated in this study the role of the MEK/extracellular signal-regulated kinase (ERK) pathway in the control of self-renewal and tumorigenicity of glioblastoma CSLCs, particularly in relation to the PI3K/mTOR (mammalian target of rapamycin) pathway. Targeted inactivation of MEK alone using pharmacological inhibitors or siRNAs resulted in reduced sphere formation of both cell line-and patient-derived glioblastoma CSLCs, accompanied by their differentiation into neuronal and glial lineages. Interestingly, this effect of MEK inactivation was apparently augmented in the presence of NVP-BEZ235, a dual inhibitor of PI3K and mTOR. As a potential explanation for this observed synergy, we found that inactivation of either the MEK/ERK or PI3K/mTOR pathway triggered activation of the other, suggesting that there may be mutually inhibitory crosstalk between these two pathways. Significantly, inactivation of either pathway led to the reduced activation of p70S6K, and siRNA-mediated knockdown of p70S6K resulted in the activation of both pathways, which no longer maintained the cross-inhibitory relationship. Finally, combinational blockade of both pathways in glioblastoma CSLCs suppressed their tumorigenicity, whether transplanted subcutaneously or intracranially, more efficiently than blockade of either alone. Our findings suggest that there is p70S6K-mediated, cross-inhibitory regulation between the MEK/ERK and PI3K/mTOR pathways, in which each contribute to the maintenance of the self-renewal and tumorigenic capacity of glioblastoma CSLCs. Thus, combinational disruption of these pathways would be a rational and effective strategy in the treatment of glioblastoma. STEM CELLS 2010;28:1930-1939