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Chemical genomics reveals inhibition of breast cancer lung metastasis by Ponatinib via c-Jun
Protein & Cell ; (12): 161-177, 2019.
Article in English | WPRIM | ID: wpr-757968
ABSTRACT
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 (HTS) 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.

Full text: Available Index: WPRIM (Western Pacific) Type of study: Prognostic study Language: English Journal: Protein & Cell Year: 2019 Type: Article

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Full text: Available Index: WPRIM (Western Pacific) Type of study: Prognostic study Language: English Journal: Protein & Cell Year: 2019 Type: Article