Role of p53/p21Waf1/Cip1 in the regulation of polyamine analogue-induced growth inhibition and cell death in human breast cancer cells
Role of p53/p21Waf1/Cip1 in the regulation of polyamine analogue-induced growth inhibition and cell death in human breast cancer cells
复制标题
DOI：
10.4161/cbt.4.9.1970
复制
发表时间：
2005-09-01
影响因子：
3.6
通讯作者：
Davidson, NE
中科院分区：
文献类型：
--
作者：
Huang, Y;Pledgie, A;Davidson, NE
细胞内多胺是细胞增殖所必需的，许多肿瘤对多胺有异常的需求。因此，多胺代谢途径是一个合理的目标，为糖尿病干预。许多多胺类似物作为细胞多胺代谢的有效调节剂，在细胞培养和动物研究中表现出令人鼓舞的抗肿瘤生长作用。在这项研究中，我们证明了特定的多胺类似物对人乳腺癌MCF-7细胞的生长表现出不同的抑制作用。用寡胺类似物和对称取代的双（烷基）取代类似物BENSpm处理MCF-7细胞，产生G（1）细胞周期停滞，而不对称取代的双（烷基）取代类似物CHENSpm诱导G（2）/M细胞周期停滞。所有四种化合物均显著上调MCF- 7细胞中p53和p21的表达。稳定转染靶向p53的小干扰RNA（siRNA）阻断了多胺类似物诱导的p21表达，并显著降低了多胺类似物诱导的生长抑制和凋亡，表明多胺类似物诱导的p21表达是通过p53依赖性机制发生的。类似物暴露对细胞周期蛋白和细胞周期蛋白依赖性激酶的影响随所用的特定试剂而变化。p53 siRNA的表达仅逆转了BENSpm调节的细胞周期阻滞，表明多胺类似物诱导的p53/p21对细胞周期阻滞的调节是通过特异性机制发生的。了解p53介导的细胞对多胺类似物的反应机制有助于提高多胺类似物对人乳腺癌的治疗效果。
Intracellular polyamines are absolutely required for cell proliferation and many tumors have abnormal requirements for polyamines. Therefore, the polyamine metabolic pathway represents a rational target for antineoplastic intervention. A number of polyamine analogues act as potent modulators of cellular polyamine metabolism and exhibit encouraging effects against tumor growth in both cell culture and animal studies. In this study we demonstrate that specific polyamine analogues exhibit differential inhibitory action against growth of human breast cancer MCF-7 cells. Treatment of MCF-7 cells with oligoamine analogues and the symmetrically substituted bis(alkyl)-substituted analogue, BENSpm, produced a G(1) cell cycle arrest, while the unsymmetrically substituted bis(alkyl)substituted analogue, CHENSpm, induced a G(2)/M cell cycle arrest. All four compounds significantly upregulated p53 and p21 expression in MCF- 7 cells. Stable transfection of small interfering RNA (siRNA) targeting p53 blocked the expression of p21 induced by the polyamine analogues and significantly reduced polyamine analogue-induced growth inhibition and apoptosis, suggesting that polyamine analogue-induced p21 expression occurs through p53-dependent mechanisms. The effects of analogue exposure on cyclins and cyclin dependent kinases varied with the specific agent used. Expression of p53 siRNA reversed only BENSpm-modulated the cell cycle arrest, suggesting that regulation of cell cycle arrest by p53/p21 induced by polyamine analogues occurs through agent-specific mechanisms. Understanding the mechanism of p53-mediated cellular responses to polyamine analogue may help to improve the therapeutic efficacy of polyamine analogues in human breast cancer.