Downregulation of Mcl-1 by daunorubicin pretreatment reverses resistance of breast cancer cells to TNF-related apoptosis-inducing ligand.

Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea.
Biochemical and Biophysical Research Communications (Impact Factor: 2.41). 04/2012; 422(1):42-7. DOI:10.1016/j.bbrc.2012.04.093
Source: PubMed

ABSTRACT The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapeutic agent. However, tumor cells often develop resistance to TRAIL, limiting its therapeutic potential. To study the mechanism underlying TRAIL-resistance in breast cancer cells, we performed a high-throughput compound screen in MCF-7 cells. We identified daunorubicin as a potent sensitizer of TRAIL-induced apoptosis in MCF-7 cells. Daunorubicin in combination with subtoxic concentrations of recombinant human TRAIL induced massive apoptosis in MCF-7 cells. This combination was effective in TRAIL-resistant MDA-MB-231 and T47D breast cancer cells. By immunoblotting, we found that daunorubicin treatment induced loss of the anti-apoptotic protein, Mcl-1, in breast cancer cells. RNA interference experiments revealed that reduced expression of Mcl-1 sensitized MCF-7 cells to TRAIL. Together, these data suggest that Mcl-1 is a major contributor to TRAIL-resistance in breast cancer cells, and that reduction of Mcl-1 protein levels using DNA damaging agents is a promising approach for cancer therapy.

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