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. 2013 Jan;46(1):59-64.
doi: 10.5483/bmbrep.2013.46.1.123.

Antiproliferative effect of gold(I) compound auranofin through inhibition of STAT3 and telomerase activity in MDA-MB 231 human breast cancer cells

Nam-Hoon Kim  1 , Hyo Jung Park, Mi-Kyung Oh, In-Sook Kim
Affiliations

Antiproliferative effect of gold(I) compound auranofin through inhibition of STAT3 and telomerase activity in MDA-MB 231 human breast cancer cells

Nam-Hoon Kim et al. BMB Rep. 2013 Jan.

Abstract

Signal transducer and activator of transcription 3 (STAT3) and telomerase are considered attractive targets for anticancer therapy. The in vitro anticancer activity of the gold(I) compound auranofin was investigated using MDA-MB 231 human breast cancer cells, in which STAT3 is constitutively active. In cell culture, auranofin inhibited growth in a dose-dependent manner, and N-acetyl-L-cysteine (NAC), a scavenger of reactive oxygen species (ROS), markedly blocked the effect of auranofin. Incorporation of 5-bromo-2'-deoxyuridine into DNA and anchorage-independent cell growth on soft agar were decreased by auranofin treatment. STAT3 phosphorylation and telomerase activity were also attenuated in cells exposed to auranofin, but NAC pretreatment restored STAT3 phosphorylation and telomerase activity in these cells. These findings indicate that auranofin exerts in vitro antitumor effects in MDA-MB 231 cells and its activity involves inhibition of STAT3 and telomerase. Thus, auranofin shows potential as a novel anticancer drug that targets STAT3 and telomerase.

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Figures

Fig. 1.
Fig. 1.. Growth inhibition of MDA-MB 231 cells by auranofin. MDA-MB 231 cells were seeded in 96-well plates (1 × 104/well) and incubated overnight. (A) Cells were treated with auranofin (0.3-2 μM) and cultured for 12-72 h. At the indicated times, viable cells were determined by the MTT assay. (B) After preincubation with 10 mM NAC for 30 min, the cells were cultured in the presence of 1 μM auranofin for the indicated times, and then MTT assay was performed. Results are expressed as mean ± standard deviation (SD) of triplicate wells. Experiments were performed three times with similar results.
Fig. 2.
Fig. 2.. The inhibitory effect of auranofin on MDA-MB 231 cell proliferation. Cells were treated with auranofin (0.5 or 1 μM) and incubated for 24 or 48 h. BrdU (10 μM) was added to each culture 30 min before the end of incubation. To detect BrdU incorporation into DNA, immunocytochemistry was carried out using anti-BrdU antibodies and Alexa Fluor 488-conjugated secondary antibodies as described in Materials and Methods. DAPI staining was performed simultaneously. The stained cells were observed using a fluorescence microscope and photographed (×200). Experiments were performed twice with similar results, and representative results are shown.
Fig. 3.
Fig. 3.. Inhibition of anchorage-independent growth of MDA-MB 231 cells by auranofin. Cells were treated with auranofin (0.5 or 1 μM) for 24 or 48 h. After harvesting cells and suspending them in culture medium containing 0.3% soft agar, the cells were plated over a 0.6% bottom agar layer. The cells were cultured for 14 days, and the 1 ml culture medium covering the top agar layer was changed every 3 days. (A) Colonies that formed in the soft agar were stained with 1 mg/ml MTT. (B) Colonies in three random fields of each well were counted and expressed as a ratio to the untreated control cells. Results are expressed as mean ± SD of three separate experiments. **P ＜ 0.005, ***P ＜ 0.0005 versus untreated control.
Fig. 4.
Fig. 4.. Inhibition of STAT3 and telomerase activity in auranofin-treated MDA-MB 231 cells. Cells were treated with 1 μM auranofin for the indicated times (A) or treated for 12 h with increasing auranofin concentrations (0.3, 0.5, or 1 μM) (B). (C) Cells were preincubated with 10 mM NAC for 30 min before auranofin treatment (1 μM) for 5 h. Using cell lysates, STAT3 and tyrosine-phosphorylated STAT3 (PY-STAT3) were detected by Western blot analysis. (D) Cells were preincubated for 30 min in the absence or presence of 10 mM NAC and then exposed to 1 μM auranofin for 12 or 24 h. Telomerase activity was determined using the TRAPeze telomerase detection kit as described in Materials and Methods. Positive and negative controls were the cell extract from telomerase-positive cells supplied in the kit and heat-inactivated (85℃ for 10 min) positive cell extract, respectively. All experiments were carried out three times with similar results
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