KMID : 0613820130230101230
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Journal of Life Science 2013 Volume.23 No. 10 p.1230 ~ p.1238
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Tumor-suppressor Protein p53 Sensitizes Human Colorectal Carcinoma HCT116 Cells to 17¥á-estradiol-induced Apoptosis via Augmentation of Bak/Bax Activation
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Han Cho-Rong
Lee Ji-Young Kim Dong-Ki Kim Hyo-Young Kim Se-Jin Jang Seok-joon Kim Yoon-Hee Jun Do-Youn Kim Young-Ho
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Abstract
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The regulatory effect of the tumor-suppressor protein p53 on the apoptogenic activity of 17¥á-estradiol (17¥á-E©ü) was compared between HCT116 (p53+/+) and HCT116 (p53-/-) cells. When the HCT116 (p53+/+) and HCT116 (p53-/-) cells were treated with 2.5~10¥ìM 17¥á-E©ü for 48 h or with 10¥ìMfor various time periods, cytotoxicity and an apoptotic sub-G©û peak were induced in the HCT116 (p53+/+) cells in a dose- and time-dependent manner. However, the HCT116 (p53-/-) cells were much less sensitive to the apoptotic effect of 17¥á-E©ü. Although 17¥á-E©ü induced aberrant mitotic spindle organization and incomplete chromosome congregation at the equatorial plate, G©ü/M arrest was induced to a similar extent in both cell types. In addition, 17¥á-E©ü-induced activation of Bak and Bax, ¡â¥÷m loss, and PARP degradation were more dominant in the HCT116 (p53+/+) than in the HCT116 (p53-/-) cells. In accordance with enhancement of p53 phosphorylation (Ser-15) and p53 levels, p21 and Bax levels were elevated in the HCT116 (p53+/+) cells treated with 17¥á-E©ü. The HCT116 (p53-/-) cells exhibited barely or undetectable levels of p21 and Bax, regardless of 17¥á-E©ü treatment. On the other hand, although the level of Bcl-2 was slightly lower in the HCT116 (p53+/+) than in the HCT116 (p53-/-) cells, it remained relatively constant after the 17¥á-E©ü treatment. Together, these results show that among the components of the 17¥á-E©ü-induced apoptotic-signaling pathway, which proceeds through mitotic spindle defects causing mitotic arrest, subsequent activation of Bak and Bax and the mitochondria-dependent caspase cascade, leading to PARP degradation, 17¥á-E©ü-induced activation of Bak and Bax is the upstream target of proapoptotic action of p53.
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KEYWORD
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17¥á-estradiol, mitotic arrest, activation of Bak and Bax, p53 phosphorylation (Ser-15), mitochondrial apoptosis
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