Inhibition of neuroblastoma proliferation by PF-3758309, a small-molecule inhibitor that targets p21-activated kinase 4.
Inhibition of neuroblastoma proliferation by PF-3758309, a small-molecule inhibitor that targets p21-activated kinase 4.
复制标题
PF-3758309（一种针对 p21 激活激酶 4 的小分子抑制剂）抑制神经母细胞瘤增殖
DOI：
10.3892/or.2017.5989
复制
发表时间：
2017-11
期刊：
影响因子：
4.2
通讯作者：
Pan J
中科院分区：
文献类型：
--
作者：
Li Z;Li X;Xu L;Tao Y;Yang C;Chen X;Fang F;Wu Y;Ding X;Zhao H;Li M;Qian G;Xu Y;Ren J;Du W;Wang J;Lu J;Hu S;Pan J
神经母细胞瘤是儿童最常见的颅外实体肿瘤。尽管有先进的多模式治疗，但高危患者的生存率仍然很低。p21活化激酶4 （PAK4）已被证明在癌细胞中调节许多细胞过程，包括迁移、极化和增殖。然而，PAK4在神经母细胞瘤中的作用尚不清楚。在本研究中，我们证实PAK4在神经母细胞瘤组织中过表达，并与肿瘤的恶性及预后相关。为了研究PAK4在神经母细胞瘤中的功能，我们使用了一种靶向PAK4的小分子抑制剂PF-3758309。结果表明，PF-3758309可显著诱导成神经细胞瘤细胞系细胞周期阻滞于G1期和细胞凋亡。同时，PF-3758309对PAK4的抑制使CDKN1A、BAD和BAK1的表达增加，Bcl-2和Bax的表达降低。此外，我们通过PCR阵列筛选PAK4的靶基因，发现PF-3758309抑制PAK4后，23个基因表达上调（包括TP53I3、TBX3、EEF1A2、CDKN1A、IFNB1和MAPK8IP2）， 20个基因表达下调（包括TNFSF8、Bcl2-A1、Bcl2L1、SOCS3、BIRC3和NFKB1）。此外，PAK4通过ERK信号通路调控细胞周期和凋亡。总之，本研究首次证实了PAK4在神经母细胞瘤中的表达和功能，以及PF-3758309的抑制作用，值得进一步研究其作为神经母细胞瘤治疗的替代策略。
Neuroblastoma is the most common extracranial solid childhood tumor. Despite the availability of advanced multimodal therapy, high-risk patients still have low survival rates. p21-activated kinase 4 (PAK4) has been shown to regulate many cellular processes in cancer cells, including migration, polarization and proliferation. However, the role of PAK4 in neuroblastoma remains unclear. In the present study, we demonstrated that PAK4 was overexpressed in neuroblastoma tissues and was correlated with tumor malignance and prognosis. To investigate the function of PAK4 in neuroblastoma, we used a small-molecule inhibitor that targets PAK4, that is, PF-3758309. Our results showed that PF-3758309 significantly induced cell cycle arrest at the G1 phase and apoptosis in neuroblastoma cell lines. Meanwhile, the inhibition of PAK4 by PF-3758309 increased the expression of CDKN1A, BAD and BAK1 and decreased the expression of Bcl-2 and Bax. In addition, we screened the target genes of PAK4 by PCR array and found that 23 genes were upregulated (including TP53I3, TBX3, EEF1A2, CDKN1A, IFNB1 and MAPK8IP2) and 20 genes were downregulated (including TNFSF8, Bcl2-A1, Bcl2L1, SOCS3, BIRC3 and NFKB1) after PAK4 inhibition by PF-3758309. Moreover, PAK4 was found to regulate the cell cycle and apoptosis via the ERK signaling pathway. In conclusion, the present study demonstrated, for the first time, the expression and function of PAK4 in neuroblastomas and the inhibitory effect of PF-3758309, which deserves further investigation as an alternative strategy for neuroblastoma treatment.
登录
查看更多内容
影响因子：
9
作者：
通讯作者：
--
DOI：
10.5402/2012/694201
发表时间：
2012
期刊：
ISRN oncology
影响因子：
--
作者：
Minden A
通讯作者：
Minden A
影响因子：
11.4
作者：
Abo, A;Qu, J;Minden, A
通讯作者：
Minden, A
影响因子：
5.3
作者：
Paliouras, Grigorios N.;Naujokas, Monica A.;Park, Morag
通讯作者：
Park, Morag
影响因子：
11.2
作者：
Franovic A;Elliott KC;Seguin L;Camargo MF;Weis SM;Cheresh DA
通讯作者：
Cheresh DA