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p-21 activated kinase 4 promotes proliferation and survival of pancreatic cancer cells through AKT- and ERK-dependent activation of NF-κB pathway

机译:p-21活化的激酶4通过AKT和ERK依赖性的NF-κB途径促进胰腺癌细胞的增殖和存活

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摘要

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.
机译:鉴定新的分子靶标并了解胰腺癌(PC)侵略性的潜在机制仍然是研究的主要重点。在这里,我们研究了p21活化激酶4(PAK4)的表达及其病理生物学意义,该基因先前在PC子集中被扩增。我们的数据表明PAK4在PC组织和细胞系中过度表达,而在正常胰腺中几乎没有表达。 RNA干扰使两种PC细胞系MiaPaCa和T3M4中的PAK4沉默,归因于细胞周期进程的减少和凋亡抗性,导致生长和克隆形成能力受到抑制。 PAK4沉默的PC细胞表现出与增殖和生存相关的蛋白质的表达改变。此外,我们观察到PAK4沉默的PC细胞中NF-κB的核蓄积和转录活性下降,与其抑制蛋白IκBα的稳定有关。用IKKBα的上游激酶IKKβ的组成型活性突变体转染PAK4沉默的PC细胞可导致NF-κB活性和PC细胞生长的恢复。此外,我们表明,PAK4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,PAK4是PC细胞中NF-κB通路的调节剂,可以作为治疗的新靶标。

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