TPA-induced p21 expression augments G2/M arrest through a p53-independent mechanism in human breast cancer cells
TPA-induced p21 expression augments G2/M arrest through a p53-independent mechanism in human breast cancer cells
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DOI：
10.3892/or.2011.1511
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发表时间：
2012-02-01
期刊：
影响因子：
4.2
通讯作者：
Lee, Jeong Eon
中科院分区：
文献类型：
--
作者：
Han, Jeonghun;Kim, Sangmin;Lee, Jeong Eon
肿瘤促进剂12-O-十四酰佛波醇-13-乙酸酯(TPA)在多种肿瘤细胞中对细胞周期的调节作用不同。TPA与乳腺癌细胞周期之间的机制尚不完全清楚。因此，我们研究了TPA对乳腺癌细胞周期的调控机制。我们的结果显示，TPA以剂量依赖的方式增加野生型p53的MCF-7细胞和突变型p53的MDA-MB-231细胞中p21的表达水平。相反，TPA可降低MCF-7细胞中P53的表达，但不影响MDA-MB-231细胞。接下来，我们研究了TPA对p21和p53表达的调节机制。我们的结果表明，尽管TPA增加了MCF-7细胞ERK和JNK的磷酸化，但MEK1/2抑制剂UO126可逆转TPA诱导的p21上调和p53下调，而JNK抑制剂SP600125和p38抑制剂SB203580则不能逆转这一作用。此外，TPA诱导的G2/M期阻滞也可被UO126恢复。为了证实p21通过MEK/ERK途径的表达，我们用构件活性(CA)-MEK腺病毒感染细胞。结果表明，CA-MEK过表达可显著上调p21的表达。综上所述，我们认为TPA通过MEK/ERK依赖的途径相互调节p21和p53的表达水平。在乳腺癌细胞中，p21对TPA的上调是通过一种不依赖于p53的机制来实现的。
The tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA), has a differential role on the regulation of the cell cycle in a variety of tumor cells. The mechanism between TPA and the cell cycle in breast cancer is not fully understood. Therefore, we investigated the regulatory mechanism of TPA on control of the cell cycle of breast cancer cells. Our results showed that TPA increased the level of p21 expression in MCF-7 cells with wild-type p53 and MDA-MB-231 cells with mutant p53 in a dose-dependent manner. In contrast, TPA decreased the expression of p53 in MCF-7 cells, but did not affect MDA-MB-231 cells. We next examined the regulatory mechanism of TPA on p21 and p53 expression. Our results showed that the TPA-induced up-regulation of p21 and down-regulation of p53 was reversed by UO126 (a MEK1/2 inhibitor), but not by SP600125 (a JNK inhibitor) or SB203580 (a p38 inhibitor), although TPA increased the phosphorylation of ERK and JNK in MCF-7 cells. In addition, the TPA-induced arrest of the G2/M phase was also recovered by UO126 treatment. To confirm the expression of p21 through the MEK/ERK pathway, cells were transfected with constitutively active (CA)-MEK adenovirus. Our results showed that the expression of p21 was significantly increased by CA-MEK overexpression. Taken together, we suggest that TPA reciprocally regulates the level of p21 and p53 expression via a MEK/ERK-dependent pathway. The up-regulation of p21 in response to TPA is mediated through a p53-independent mechanism in breast cancer cells.