Kruppel-like Pluripotency Factors as Modulators of Cancer Cell Therapeutic Responses.
Kruppel-like Pluripotency Factors as Modulators of Cancer Cell Therapeutic Responses.
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DOI：
10.1158/0008-5472.can-15-1806
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发表时间：
2016-04-01
期刊：
影响因子：
11.2
通讯作者：
Ruppert JM
中科院分区：
文献类型：
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作者：
Farrugia MK;Vanderbilt DB;Salkeni MA;Ruppert JM
肿瘤细胞从其正常前体中继承了广泛的应激反应机制，该机制对于应对包括氧化应激、创伤和剪切应力在内的挑战而存活至关重要。Kruppel样转录因子，包括KLF4和KLF5，在肿瘤发生过程中很少受到遗传改变的影响，但在正常和肿瘤细胞中构成应激反应机制的关键组成部分，并与关键的生存途径，包括RAS，p53，生存素和BCL 2家族的细胞死亡调节因子相互作用。在肿瘤细胞内，KLF4和KLF5在肿瘤细胞命运、调节细胞增殖、细胞存活和癌症干细胞样细胞的肿瘤起始性质中起关键作用。这些因子可以优先在胚胎干细胞或癌症干细胞样细胞中表达。事实上，特定的KLF代表了胚胎干细胞中交叉调节多能性网络的关键组分，并且当在成体细胞中与其他Yamanaka因子共表达时诱导多能性。最近的研究表明，这种多能性网络与响应靶向治疗而发生的癌细胞适应性重编程之间存在相似性，将KLF4和KLF5与HER2靶向治疗诱导的适应性促生存信号传导反应联系起来。我们回顾文献支持KLF作为应激适应和细胞重编程的共同机制，并解决治疗意义。
Tumor cells inherit from their normal precursors an extensive stress response machinery that is critical for survival in response to challenges including oxidative stress, wounding and shear stress. Kruppel-like transcription factors, including KLF4 and KLF5, are rarely affected by genetic alteration during tumorigenesis, but compose key components of the stress response machinery in normal and tumor cells and interact with critical survival pathways, including RAS, p53, survivin and the BCL2 family of cell death regulators. Within tumor cells KLF4 and KLF5 play key roles in tumor cell fate, regulating cell proliferation, cell survival and the tumor initiating properties of cancer stem-like cells. These factors can be preferentially expressed in embryonic stem cells or cancer stem-like cells. Indeed, specific KLFs represent key components of a cross regulating pluripotency network in embryonic stem cells, and induce pluripotency when coexpressed in adult cells with other Yamanaka factors. Suggesting analogies between this pluripotency network and the cancer cell adaptive reprogramming that occurs in response to targeted therapy, recent studies link KLF4 and KLF5 to adaptive prosurvival signaling responses induced by HER2-targeted therapy. We review literature supporting KLFs as shared mechanisms in stress adaptation and cellular reprogramming and address the therapeutic implications.