期刊
PROTEIN & CELL
卷 10, 期 3, 页码 161-177出版社
OXFORD UNIV PRESS
DOI: 10.1007/s13238-018-0533-8
关键词
anti-metastatic drug discovery; gene expression signature; high-throughput sequencing-based high-throughput screening; Ponatinib; breast cancer lung metastasis; c-Jun
类别
资金
- National Natural Science Foundation of China [81673460]
- Tsinghua-Peking Joint Center for Life Sciences
- Beijing Municipal Science & Technology Commission
Metastasis is the leading cause of human cancer deaths. Unfortunately, no approved drugs are available for anti-metastatic treatment. In our study, high-throughput sequencing-based high-throughput screening (HTS2) and a breast cancer lung metastasis (BCLM)-associated gene signature were combined to discover anti-metastatic drugs. After screening of thousands of compounds, we identified Ponatinib as a BCLM inhibitor. Ponatinib significantly inhibited the migration and mammosphere formation of breast cancer cells in vitro and blocked BCLM in multiple mouse models. Mechanistically, Ponatinib represses the expression of BCLM-associated genes mainly through the ERK/c-Jun signaling pathway by inhibiting the transcription of JUN and accelerating the degradation of c-Jun protein. Notably, JUN expression levels were positively correlated with BCLM-associated gene expression and lung metastases in breast cancer patients. Collectively, we established a novel approach for the discovery of anti-metastatic drugs, identified Ponatinib as a new drug to inhibit BCLM and revealed c-Jun as a crucial factor and potential drug target for BCLM. Our study may facilitate the therapeutic treatment of BCLM as well as other metastases.
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