Tumor-suppressor Protein p53 Sensitizes Human Colorectal Carcinoma HCT116 Cells to 17α-estradiol-induced Apoptosis via Augmentation of Bak/Bax Activation

Abstract

The regulatory effect of the tumor-suppressor protein p53 on the apoptogenic activity of 17α-estradiol (17α-E2) was compared between HCT116 (p53 ) cells were treated with 2.5~10 μM 17α-E2 for 48 h or with 10 μM for various time periods, cytotoxicity and an apoptotic sub-G1 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 17α-E2. Although 17α-E2 induced aberrant mitotic spindle organization and incomplete chromosome congregation at the equatorial plate, G2/M arrest was induced to a similar extent in both cell types. In addition, 17α-E2-induced activation of Bak and Bax, Δψm loss, and PARP degradation were more dominant in the HCT116 (p53 ) cells, it remained relatively constant after the 17α-E2 treatment. Together, these results show that among the components of the 17α-E2-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, 17α-E2-induced activation of Bak and Bax is the upstream target of proapoptotic action of p53.