PI3K p110β isoform synergizes with JNK in the regulation of glioblastoma cell proliferation and migration through Akt and FAK inhibition.
PI3K p110β isoform synergizes with JNK in the regulation of glioblastoma cell proliferation and migration through Akt and FAK inhibition.
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PI3KP110β同工型与JNK协同通过AKT和FAK抑制来调节胶质母细胞瘤细胞增殖和迁移。
DOI：
10.1186/s13046-016-0356-5
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发表时间：
2016-05-12
期刊：
影响因子：
--
通讯作者：
To SS
中科院分区：
文献类型：
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作者：
Zhao HF;Wang J;Jiang HR;Chen ZP;To SS
多形性胶质母细胞瘤是最具侵袭性的恶性原发性脑肿瘤，其特征是快速生长并广泛浸润邻近的正常脑实质。 PI3K/Akt 和 JNK 通路对于胶质母细胞瘤细胞的存活、迁移和侵袭至关重要。由于 PI3K 和 JNK 在胶质母细胞瘤细胞中过度激活，因此成为胶质母细胞瘤治疗的有希望的靶标。为了研究 IA 类 PI3K 催化异构体（p110α、p110β 和 p110δ）和 JNK 抑制对肿瘤细胞生长和运动的联合作用，用异构体选择性 PI3K 抑制剂与 JNK 抑制剂联合治疗胶质母细胞瘤细胞和裸鼠异种移植物。我们发现，这些 PI3K 亚型和 JNK 的联合抑制对体外胶质母细胞瘤细胞的增殖、迁移和侵袭产生不同的影响。药理学抑制 p110β 或 p110δ（而非 p110α）与 JNK 抑制通过降低 Akt、FAK 和 zyxin 的磷酸化对胶质母细胞瘤细胞增殖和迁移产生协同抑制作用，从而阻断片状伪足和膜皱褶的形成。所有联合治疗均未观察到对侵袭的协同作用。在体内，与单独使用单一抑制剂相比，p110β 和 JNK 抑制剂的组合显着减少了异种移植肿瘤的生长。同时抑制 p110β 和 JNK 在抑制体外胶质母细胞瘤细胞增殖和迁移以及体内异种移植肿瘤生长方面表现出协同作用。我们的数据表明，PI3K p110β 同工型和 JNK 的联合抑制可能成为多形性胶质母细胞瘤的有效且有前景的治疗方法。本文的在线版本 (doi:10.1186/s13046-016-0356-5) 包含补充材料，可供授权用户使用。
Glioblastoma multiforme is the most aggressive malignant primary brain tumor, characterized by rapid growth and extensive infiltration to neighboring normal brain parenchyma. Both PI3K/Akt and JNK pathways are essential to glioblastoma cell survival, migration and invasion. Due to their hyperactivation in glioblastoma cells, PI3K and JNK are promising targets for glioblastoma treatment. To investigate the combination effects of class IA PI3K catalytic isoforms (p110α, p110β and p110δ) and JNK inhibition on tumor cell growth and motility, glioblastoma cells and xenografts in nude mice were treated with isoform-selective PI3K inhibitors in combination with JNK inhibitor. We showed that combined inhibition of these PI3K isoforms and JNK exerted divergent effects on the proliferation, migration and invasion of glioblastoma cells in vitro. Pharmacological inhibition of p110β or p110δ, but not p110α, displayed synergistic inhibitory effect with JNK inhibition on glioblastoma cell proliferation and migration through decreasing phosphorylation of Akt, FAK and zyxin, leading to blockade of lamellipodia and membrane ruffles formation. No synergistic effect on invasion was observed in all the combination treatment. In vivo, combination of p110β and JNK inhibitors significantly reduced xenograft tumor growth compared with single inhibitor alone. Concurrent inhibition of p110β and JNK exhibited synergistic effects on suppressing glioblastoma cell proliferation and migration in vitro and xenograft tumor growth in vivo. Our data suggest that combined inhibition of PI3K p110β isoform and JNK may serve as a potent and promising therapeutic approach for glioblastoma multiforme. The online version of this article (doi:10.1186/s13046-016-0356-5) contains supplementary material, which is available to authorized users.