[논문]Tetrabromobisphenol A Induces MMP-9 Expression via NADPH Oxidase and the activation of ROS, MAPK, and Akt Pathways in Human Breast Cancer MCF-7 Cells

Lee, Gi Ho; Jin, Sun Woo; Kim, Se Jong; Pham, Thi Hoa; Choi, Jae Ho; Jeong, Hye Gwang

doi:10.5487/tr.2019.35.1.093

Tetrabromobisphenol A Induces MMP-9 Expression via NADPH Oxidase and the activation of ROS, MAPK, and Akt Pathways in Human Breast Cancer MCF-7 Cells 원문보기

Toxicological research, v.35 no.1, 2019년, pp.93 - 101

Lee, Gi Ho (Department of Toxicology, College of Pharmacy, Chungnam National University) , Jin, Sun Woo (Department of Toxicology, College of Pharmacy, Chungnam National University) , Kim, Se Jong (Department of Toxicology, College of Pharmacy, Chungnam National University) , Pham, Thi Hoa (Department of Toxicology, College of Pharmacy, Chungnam National University) , Choi, Jae Ho (Department of Toxicology, College of Pharmacy, Chungnam National University) , Jeong, Hye Gwang (Department of Toxicology, College of Pharmacy, Chungnam National University)

Abstract ▼ AI-Helper

Tetrabromobisphenol A (TBBPA), the most common industrial brominated flame retardant, acts as a cytotoxic, neurotoxic, and immunotoxicant, causing inflammation and tumors. However, the mechanism of TBBPA-induced matrix metalloproteinase-9 (MMP-9) expression in human breast cancer cells is not clear. In human breast cancer MCF-7 cells, treatment with TBBPA significantly induced the expression and promoter activity of MMP-9. Transient transfection with MMP-9 mutation promoter constructs verified that $NF-{\kappa}B$ and AP-1 response elements are responsible for the effects of TBBPA. Furthermore, TBBPA-induced MMP-9 expression was mediated by $NF-{\kappa}B$ and AP-1 transcription activation as a result of the phosphorylation of the Akt and MAPK signaling pathways. Moreover, TBBPA-induced activation of Akt/MAPK pathways and MMP-9 expression were attenuated by a specific NADPH oxidase inhibitor, and the ROS scavenger. These results suggest that TBBPA can induce cancer cell metastasis by releasing MMP-9 via ROS-dependent MAPK, and Akt pathways in MCF-7 cells.

주제어

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가설 설정

However, scant information on the regulation of MMP-9 expression by TBBPA is available. In this study, we investigated the effect of TBBPA on the regulatory mechanism of MMP-9 expression in human breast cancer MCF-7 cells.

제안 방법

To investigate which of these transcription factors regulates MMP-9 expression in MCF-7 cells, cells were transiently transfected with reporter genes that contain the wild-type MMP-9 promoter, an NF-κB sitemutated promoter, or an AP-1 site-mutated promoter.

대상 데이터

A dual-luciferase assay system was obtained from Promega (Madison, WI, USA). Inhibitors against LY294002, PD98059, SB203580, and SP600125 were obtained from Calbiochem (La Jolla, CA, USA). Primary antibodies against phospho-Akt, phospho- ERKl/2, phospho-p38 MAPK, phospho-JNK1/2, ERKl/2, p38 MAPK, JNK1/2, and secondary antibodies against horseradish peroxidase (HRP)-linked anti-mouse or antirabbit IgG were obtained from Cell Signaling Technologies(Beverly, MA, USA).
The TBBPA (97%) was obtained from Sigma-Aldrich (St. Louis, MO, USA). RPMI 1640, fetal bovine serum (FBS), and penicillin-streptomycin were obtained from Gibco BRL (Grand Island, NY, USA).
The human breast carcinoma MCF-7 cell line was obtained from the American Type Culture Collection (Manassas, VA, USA). The MCF-7 cells were cultured in RPMI 1640 supplemented with 10% FBS, 100μg/mL streptomycin, and 100 U/mL penicillin in a humidified atmosphere of 5% CO₂ at 37℃.

데이터처리

All data were demonstrated as means ± SD from at least three representative tests. Statistical significance was assessed by one-way analysis of variance (ANOVA) followed by the Tukey-Kramer test. A value of p < 0.

이론/모형

The activity of NADPH oxidase by TBBPA in MCF-7 cells was determined using the lucigenin chemiluminescence method. After treatment with TBBPA or vehicle for the indicated period of time, cells were gently scraped and centrifuged for 10 min at 4℃.

성능/효과

In conclusion, our study demonstrated that TBBPA induced MMP-9 expression via ROS-dependent Akt/MAPK signaling pathways, which was mediated via increased NF-κB and AP-1 activation in MCF-7 cells.

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