Functional Role and Therapeutic Potential of the Pim-1 Kinase in Colon Carcinoma
Functional Role and Therapeutic Potential of the Pim-1 Kinase in Colon Carcinoma
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DOI：
10.1593/neo.13172
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发表时间：
2013-07-01
期刊：
影响因子：
4.8
通讯作者：
Aigner, Achim
中科院分区：
文献类型：
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作者：
Weirauch, Ulrike;Beckmann, Nadine;Aigner, Achim
目得：莫洛尼鼠白血病病毒1（Pim-1）激酶的前病毒整合位点在各种肿瘤中过表达，并与预后不良有关。其作为原癌基因的作用是基于参与关键细胞过程的几种Pim-1靶蛋白。在这里，我们探讨Pim-1在结肠癌中的功能相关性。实验设计：使用基于RNAi的敲低方法以及特异性小分子抑制剂来抑制结肠癌细胞中的Pim-1。在体外和体内小鼠肿瘤模型中分析了增殖、细胞凋亡、对细胞生长抑制治疗的敏感性和总体抗肿瘤作用。结果：我们证明了Pim-1抑制的抗增殖、促凋亡和总体抗肿瘤作用。Pim-1敲低后对5-氟尿嘧啶（5-FU）治疗的敏感性为组合治疗方法提供了新的可能性。重要的是，这也拮抗了5-FU触发的Pim-1上调，这是由miR-15 b水平降低介导的，miR-15 b是我们新发现的一种调节Pim-1的microRNA。Pim-1抑制的分子效应分析揭示了一个复杂的调控网络，治疗性Pim-1抑制导致致癌信号转导的主要变化，涉及p21（Cip 1/WAF 1）、STAT 3、c-jun-N-末端激酶（JNK）、c-Myc和生存素，以及凋亡相关蛋白Puma、Bax和Bcl-xL的水平。结论：我们证明Pim-1在几个肿瘤相关信号通路中起着关键作用，并建立了Pim-1在结肠癌中的功能相关性。我们的研究结果也证实了基于聚合物聚乙烯亚胺/小干扰RNA纳米颗粒的RNAi介导的Pim-1敲低作为一种有前途的治疗方法。
PURPOSE: The provirus integration site for Moloney murine leukemia virus 1 (Pim-1) kinase is overexpressed in various tumors and has been linked to poor prognosis. Its role as proto-oncogene is based on several Pim-1 target proteins involved in pivotal cellular processes. Here, we explore the functional relevance of Pim-1 in colon carcinoma. EXPERIMENTAL DESIGN: RNAi-based knockdown approaches, as well as a specific small molecule inhibitor, were used to inhibit Pim-1 in colon carcinoma cells. The effects were analyzed regarding proliferation, apoptosis, sensitization toward cytostatic treatment, and overall antitumor effect in vitro and in mouse tumor models in vivo. RESULTS: We demonstrate antiproliferative, proapoptotic, and overall antitumor effects of Pim-1 inhibition. The sensitization to 5-fluorouracil (5-FU) treatment upon Pim-1 knockdown offers new possibilities for combinatorial treatment approaches. Importantly, this also antagonizes a 5-FU-triggered Pim-1 up-regulation, which is mediated by decreased levels of miR-15b, a microRNA we newly identify to regulate Pim-1. The analysis of the molecular effects of Pim-1 inhibition reveals a complex regulatory network, with therapeutic Pim-1 repression leading to major changes in oncogenic signal transduction with regard to p21(Cip1/WAF1), STAT3, c-jun-N-terminal kinase (JNK), c-Myc, and survivin and in the levels of apoptosis-related proteins Puma, Bax, and Bcl-xL. CONCLUSIONS: We demonstrate that Pim-1 plays a pivotal role in several tumor-relevant signaling pathways and establish the functional relevance of Pim-1 in colon carcinoma. Our results also substantiate the RNAi-mediated Pim-1 knockdown based on polymeric polyethylenimine/small interfering RNA nanoparticles as a promising therapeutic approach.