Low DEDD expression in breast cancer cells indicates higher sensitivity to the Bcl-2-specific inhibitor ABT-199

Abstract

As a proapoptotic death effect domain (DED)-containing protein, DED-containing DNA-binding protein (DEDD) has been demonstrated to inhibit tumor growth, invasion and metastasis in our previous studies. Here, we demonstrated that knockdown of DEDD in MCF-7 cells resulted in characteristic drug resistance to doxorubicin and paclitaxel, and overexpression of DEDD in MDA-MB-231 cells increased their sensitivity to doxorubicin and paclitaxel. The expression levels of DEDD were positively correlated with Bcl-2 in breast cancer cell lines as well as in human breast cancer tissue. Knockdown of DEDD downregulated the transcriptional activity of the bcl-2 gene and shortened the time for Bcl-2 degradation. DEDD interacts with and stabilizes Bcl-2, and breast cancer cells with low DEDD expression were more sensitive to treatment with a BH3 mimetic, ABT-199, than were those with high DEDD expression. In total, our findings highlight a new strategy for treating breast cancer with no/low DEDD expression by targeting Bcl-2 with the BH3 mimetic ABT-199.

Keywords: ABT-199; Bcl-2; Breast cancer; DEDD; Drug resistance.