p-21 activated kinase 4 promotes proliferation and survival of pancreatic cancer cells through AKT- and ERK-dependent activation of NF-κB pathway.
p-21 activated kinase 4 promotes proliferation and survival of pancreatic cancer cells through AKT- and ERK-dependent activation of NF-κB pathway.
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DOI：
10.18632/oncotarget.2398
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发表时间：
2014-09-30
期刊：
影响因子：
--
通讯作者：
Singh S
中科院分区：
文献类型：
--
作者：
Tyagi N;Bhardwaj A;Singh AP;McClellan S;Carter JE;Singh S
识别新的分子靶点和了解胰腺癌（PC）侵袭性的潜在机制仍然是研究的主要重点领域。在这里，我们研究了p21激活激酶4（PAK 4）的表达和病理生物学意义，PAK 4是一种早期显示在PC亚组中扩增的基因。我们的数据表明PAK 4在PC组织和细胞系中过表达，而在正常胰腺中很少或没有表达。在两种PC细胞系MiaPaCa和T3 M4中，通过RNA干扰的PAK 4沉默导致生长和克隆形成能力的抑制，这是由于细胞周期进展减少和细胞凋亡抗性。PAK 4沉默的PC细胞表现出增殖和存活相关蛋白的表达改变。此外，我们观察到在PAK 4沉默的PC细胞中NF-κB的核积累和转录活性降低，这与其抑制蛋白IκBα的稳定有关。用IκBα上游激酶IKKβ的组成型活性突变体转染PAK 4沉默的PC细胞，导致NF-κB活性和PC细胞生长的恢复。此外，我们发现PAK 4诱导的NF-κB活性是通过ERK和Akt激酶的激活和协同作用介导的。总之，这些发现表明PAK 4是PC细胞中NF-κB通路的调节剂，可以作为治疗的新靶点。
Identification of novel molecular targets and understanding the mechanisms underlying the aggressive nature of pancreatic cancer (PC) remain prime focus areas of research. Here, we investigated the expression and pathobiological significance of p21-activated kinase 4 (PAK4), a gene that was earlier shown to be amplified in a sub-set of PC. Our data demonstrate PAK4 overexpression in PC tissues and cell lines with little or no expression in the normal pancreas. PAK4 silencing in two PC cell lines, MiaPaCa and T3M4, by RNA interference causes suppression of growth and clonogenic ability due to decreased cell cycle progression and apoptosis-resistance. PAK4-silenced PC cells exhibit altered expression of proliferation- and survival-associated proteins. Moreover, we observe decreased nuclear accumulation and transcriptional activity of NF-κB in PAK4-silenced PC cells associated with stabilization of its inhibitory protein, IκBα. Transfection of PAK4-silenced PC cells with constitutively-active mutant of IKKβ, an upstream kinase of IκBα, leads to restoration of NF-κB activity and PC cell growth. Furthermore, we show that PAK4-induced NF-κB activity is mediated through activation and concerted action of ERK and Akt kinases. Together, these findings suggest that PAK4 is a regulator of NF-κB pathway in PC cells and can serve as a novel target for therapy.
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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：
2.9
作者：
Deer EL;González-Hernández J;Coursen JD;Shea JE;Ngatia J;Scaife CL;Firpo MA;Mulvihill SJ
通讯作者：
Mulvihill SJ
影响因子：
11.4
作者：
Abo, A;Qu, J;Minden, A
通讯作者：
Minden, A
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：
Arora S;Bhardwaj A;Srivastava SK;Singh S;McClellan S;Wang B;Singh AP
通讯作者：
Singh AP