title: Downregulation of Mcl-1 by daunorubicin pretreatment reverses resistance of breast cancer cells to TNF-related apoptosis-inducing ligand.
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.
authors.affiliation: Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea.
authors.forename: Bora
authors.initials: B
authors.lastname: Oh
authors.forename: SoJung
authors.initials: S
authors.lastname: Park
authors.forename: Jhang Ho
authors.initials: JH
authors.lastname: Pak
authors.forename: InKi
authors.initials: I
authors.lastname: Kim
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004249:DNA Damage; D003630:Daunorubicin / Q000494:pharmacology*; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D005260:Female; D006801:Humans; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D034622:RNA Interference; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*
chemical_list: D000903:Antibiotics, Antineoplastic; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D053221:TNF-Related Apoptosis-Inducing Ligand; D003630:Daunorubicin