Li Y, Bhuiyan M, Mohammad R M, Sarkar F H
Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, USA.
Oncogene. 1998 Dec 3;17(22):2915-20. doi: 10.1038/sj.onc.1202218.
Bcl-2, Bax and p53 gene products have been linked to programmed cell death pathways. p21WAF1 has been shown to mediate p53-induced cell cycle arrest and to inhibit cyclin-dependent kinase activity. We have analysed the expression of these genes and apoptosis induced by 12-O-tetradecanoyl-phorbol-13-acetate (TPA) in several human breast cancer cell line. We found up-regulation of p21WAF1 and Bax expressions, however, the expressions of p53 and Bcl-2 genes remained unchanged in TPA-treated cells. Furthermore, DNA ladder formation and PARP cleavage were observed after treatment for 24 h, indicating apoptotic cell death. Flow cytometry with 7-amino actinomycin D staining showed that the number of apoptotic cells increased with longer treatment of TPA. From these results, we conclude that TPA is not only a tumor promoter, but also induces apoptosis in breast cancer cells. TPA-induced apoptosis appears to be mediated through a p53-independent pathway, and the up-regulation of p21WAF1 and Bax may be the molecular mechanisms by which TPA induces apoptosis.
Bcl-2、Bax和p53基因产物与程序性细胞死亡途径相关。p21WAF1已被证明可介导p53诱导的细胞周期停滞并抑制细胞周期蛋白依赖性激酶活性。我们分析了这些基因在几种人乳腺癌细胞系中的表达以及12-氧-十四烷酰佛波醇-13-乙酸酯（TPA）诱导的细胞凋亡。我们发现p21WAF1和Bax表达上调，然而，在TPA处理的细胞中，p53和Bcl-2基因的表达保持不变。此外，处理24小时后观察到DNA梯状条带形成和PARP裂解，表明细胞发生凋亡性死亡。用7-氨基放线菌素D染色的流式细胞术显示，随着TPA处理时间延长，凋亡细胞数量增加。从这些结果我们得出结论，TPA不仅是一种肿瘤促进剂，还能诱导乳腺癌细胞凋亡。TPA诱导的细胞凋亡似乎通过一条不依赖p53的途径介导，p21WAF1和Bax的上调可能是TPA诱导细胞凋亡的分子机制。
