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

Bora Oh, So Jung Park, Jhang Ho Pak, In Ki Kim

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

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.

Original languageEnglish
Pages (from-to)42-47
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume422
Issue number1
DOIs
StatePublished - 25 May 2012

Keywords

  • Apoptosis
  • Breast cancer
  • Daunorubicin
  • Mcl-1
  • TRAIL

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