Functional cooperativity by direct interaction between PAK4 and MMP-2 in the regulation of anoikis resistance, migration and invasion in glioma.
Functional cooperativity by direct interaction between PAK4 and MMP-2 in the regulation of anoikis resistance, migration and invasion in glioma.
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DOI：
10.1038/cddis.2012.182
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发表时间：
2012-12-20
影响因子：
9
通讯作者：
中科院分区：
文献类型：
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作者：
神经胶质瘤表现出失巢抵抗，对邻近脑实质的侵袭增强，尽管使用标准疗法，但最终还是复发。我们对基质金属蛋白酶 2 (MMP-2) 敲低 4910 和 5310 人神经胶质瘤异种移植细胞中失巢凋亡敏感性增加的研究与 p21 激活激酶 4 (PAK4) 抑制有趣地相关，促使我们进一步研究 PAK4 在神经胶质瘤中的作用。在这里，我们报告 PAK4 上调与神经胶质瘤病理分级的增加呈正相关。 siRNA介导的PAK4敲低可升高失巢凋亡，并通过下调MMP-2、αvβ3-整合素和磷酸表皮生长因子受体（磷酸EGFR）来抑制侵袭和迁移。 cDNA-PCR 阵列揭示了 PAK4 敲低细胞中参与细胞增殖和粘附的必需蛋白的转录抑制。最重要的是，谷胱甘肽 S-转移酶下拉测定证明 MMP-2 是一种新的 PAK4 相互作用蛋白，可与 PAK4 激酶结构域结合。 PAK4si处理的细胞中的单独EGFR/ErbB2抑制剂和αvβ3抗体处理表明PAK4对αvβ3/EGFR存活信号的调节。 PAK4 的过表达显着逆转了两种细胞系中 MMP2si 诱导的细胞死亡。 PAK4 和 MMP-2 的同时缺失会导致失巢凋亡介导的细胞死亡，并严重抑制这些细胞的侵袭和迁移特性。 PAK4si 通过抑制肿瘤中 MMP-2、β3-整合素和磷酸化 EGFR 水平来抑制裸鼠体内肿瘤生长。我们的研究结果表明 PAK4 和 MMP-2 之间存在物理关联，并表明 PAK4/MMP-2 双重靶向在神经胶质瘤治疗中的未来治疗潜力。
Gliomas display anoikis resistance, enhanced invasion in to the adjacent brain parenchyma and eventually recur despite using the standard therapies. Our studies on increased anoikis sensitization in matrix metalloproteinase-2 (MMP-2)-knockdown 4910 and 5310 human glioma xenograft cells were interestingly correlated with p21-activated kinase 4 (PAK4) inhibition, prompting us to further investigate the role of PAK4 in glioma. Here, we report the PAK4 upregulation in positive correlation with increasing glioma pathological grades. The siRNA-mediated PAK4 knockdown elevated anoikis, and inhibited invasion and migration by downregulating MMP-2, αvβ3-integrin and phospho-epidermal growth factor receptor (phospho-EGFR). The cDNA-PCR arrays revealed a transcriptional suppression of essential proteins involved in cell proliferation and adhesion in PAK4-knockdown cells. Most importantly, glutathione S-transferase pull-down assays demonstrated the MMP-2 as a new PAK4-interacting protein which binds to PAK4 kinase domain. Individual EGFR/ErbB2 inhibitor and αvβ3 antibody treatments in PAK4si-treated cells indicated the regulation of αvβ3/EGFR survival signaling by PAK4. Overexpression of PAK4 significantly reversed the MMP2si-induced cell death in both cell lines. Codepletion of PAK4 and MMP-2 resulted in robust anoikis-mediated cell death, and severely inhibited invasive and migratory properties in these cells. PAK4si inhibited in vivo tumor growth in nude mice by inhibiting MMP-2, β3-integrin and phospho-EGFR levels in tumors. Our findings indicate a physical association between PAK4 and MMP-2, and suggest the future therapeutic potential of PAK4/MMP-2 dual targeting in glioma treatment.
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影响因子：
8
作者：
Kesanakurti, D.;Chetty, C.;Maddirela, D. Rajasekhar;Gujrati, M.;Rao, J. S.
通讯作者：
Rao, J. S.
影响因子：
11.4
作者：
Abo, A;Qu, J;Minden, A
通讯作者：
Minden, A
影响因子：
64.5
作者：
Brooks, PC;Stromblad, S;Cheresh, DA
通讯作者：
Cheresh, DA
影响因子：
4.8
作者：
Li，Zhilun;Zhang，Hongquan;Stromblad，Staffan
通讯作者：
Stromblad，Staffan
影响因子：
3.7
作者：
Kesanakurti D;Chetty C;Bhoopathi P;Lakka SS;Gorantla B;Tsung AJ;Rao JS
通讯作者：
Rao JS