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- Title
Naringenin prevents TGF-β1 secretion from breast cancer and suppresses pulmonary metastasis by inhibiting PKC activation.
- Authors
Fayun Zhang; Wenjuan Dong; Wenfeng Zeng; Lei Zhang; Chao Zhang; Yuqi Qiu; Luoyang Wang; Xiaozhe Yin; Chunling Zhang; Wei Liang; Zhang, Fayun; Dong, Wenjuan; Zeng, Wenfeng; Zhang, Lei; Zhang, Chao; Qiu, Yuqi; Wang, Luoyang; Yin, Xiaozhe; Zhang, Chunling; Liang, Wei
- Abstract
<bold>Background: </bold>Targeting the TGF-β1 pathway for breast cancer metastasis therapy has become an attractive strategy. We have previously demonstrated that naringenin significantly reduced TGF-β1 levels in bleomycin-induced lung fibrosis and effectively prevented pulmonary metastases of tumors. This raised the question of whether naringenin can block TGF-β1 secretion from breast cancer cells and inhibit their pulmonary metastasis.<bold>Methods: </bold>We transduced a lentiviral vector encoding the mouse Tgf-β1 gene into mouse breast carcinoma (4T1-Luc2) cells and inoculated the transformant cells (4T1/TGF-β1) into the fourth primary fat pat of Balb/c mice. Pulmonary metastases derived from the primary tumors were monitored using bioluminescent imaging. Spleens, lungs and serum (n = 18-20 per treatment group) were analyzed for immune cell activity and TGF-β1 level. The mechanism whereby naringenin decreases TGF-β1 secretion from breast cancer cells was investigated at different levels, including Tgf-β1 transcription, mRNA stability, translation, and extracellular release.<bold>Results: </bold>In contrast to the null-vector control (4T1/RFP) tumors, extensive pulmonary metastases derived from 4T1/TGF-β1 tumors were observed. Administration of the TGF-β1 blocking antibody 1D11 or naringenin showed an inhibition of pulmonary metastasis for both 4T1/TGF-β1 tumors and 4T1/RFP tumors, resulting in increased survival of the mice. Compared with 4T1/RFP bearing mice, systemic immunosuppression in 4T1/TGF-β1 bearing mice was observed, represented by a higher proportion of regulatory T cells and myeloid-derived suppressor cells and a lower proportion of activated T cells and INFγ expression in CD8(+) T cells. These metrics were improved by administration of 1D11 or naringenin. However, compared with 1D11, which neutralized secreted TGF-β1 but did not affect intracellular TGF-β1 levels, naringenin reduced the secretion of TGF-β1 from the cells, leading to an accumulation of intracellular TGF-β1. Further experiments revealed that naringenin had no effect on Tgf-β1 transcription, mRNA decay or protein translation, but prevented TGF-β1 transport from the trans-Golgi network by inhibiting PKC activity.<bold>Conclusions: </bold>Naringenin blocks TGF-β1 trafficking from the trans-Golgi network by suppressing PKC activity, resulting in a reduction of TGF-β1 secretion from breast cancer cells. This finding suggests that naringenin may be an attractive therapeutic candidate for TGF-β1 related diseases.
- Subjects
NARINGENIN; TRANSFORMING growth factors-beta; BREAST cancer treatment; METASTATIC breast cancer; PULMONARY fibrosis; PROTEIN kinase C; ANIMAL experimentation; BIOLOGICAL models; BREAST tumors; CELL lines; CELLULAR signal transduction; GROWTH factors; LUNG tumors; METASTASIS; MICE; FLAVANONES
- Publication
Breast Cancer Research, 2016, Vol 18, p38
- ISSN
1465-5411
- Publication type
journal article
- DOI
10.1186/s13058-016-0698-0