Chemical genomics reveals inhibition of breast cancer lung metastasis by Ponatinib via c-Jun

doi:10.1007/s13238-018-0533-8

Protein Cell

2019, Vol. 10

Issue (3) : 161-177 https://doi.org/10.1007/s13238-018-0533-8

RESEARCH ARTICLE

Chemical genomics reveals inhibition of breast cancer lung metastasis by Ponatinib via c-Jun

Wei Shao¹, Shasha Li¹, Lu Li¹, Kequan Lin¹, Xinhong Liu¹, Haiyan Wang¹, Huili Wang¹, Dong Wang^1,^2,³(

)

¹. Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
². Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Sichuan 610041, China
³. Center for Synthetic and Systems Biology, Tsinghua University, Beijing 100084, China

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Abstract

Metastasis is the leading cause of human cancer deaths. Unfortunately, no approved drugs are available for antimetastatic 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.

Keywords anti-metastatic drug discovery gene expression signature high-throughput sequencing-based high-throughput screening Ponatinib breast cancer lung metastasis c-Jun

Corresponding Author(s): Dong Wang

Issue Date: 21 February 2019

Cite this article:

Wei Shao,Shasha Li,Lu Li, et al. Chemical genomics reveals inhibition of breast cancer lung metastasis by Ponatinib via c-Jun[J]. Protein Cell, 2019, 10(3): 161-177.

URL:

https://academic.hep.com.cn/pac/EN/10.1007/s13238-018-0533-8
https://academic.hep.com.cn/pac/EN/Y2019/V10/I3/161

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[1]	Tomohiko Tsuge, Suchithra Menon, Yingchun Tong, Ning Wei. CSN1 inhibits c-Jun phosphorylation and down-regulates ectopic expression of JNK1[J]. Prot Cell, 2011, 2(5): 423-432.
[2]	Qinghang Meng, Ying Xia. c-Jun, at the crossroad of the signaling network[J]. Prot Cell, 2011, 2(11): 889-898.

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