Oncotarget

Research Papers:

Rhodomycin A, a novel Src-targeted compound, can suppress lung cancer cell progression via modulating Src-related pathways

Yi-Hua Lai, Min-Hsuan Chen, Sih-Yin Lin, Sheng-Yi Lin, Yung-Hao Wong, Sung-Liang Yu, Huei-Wen Chen, Chih-Hsin Yang, Gee-Chen Chang and Jeremy J.W. Chen _

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Oncotarget. 2015; 6:26252-26265. https://doi.org/10.18632/oncotarget.4761

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Abstract

Yi-Hua Lai1,2,*, Min-Hsuan Chen1,*, Sih-Yin Lin1, Sheng-Yi Lin1,3, Yung-Hao Wong1, Sung-Liang Yu4, Huei-Wen Chen5, Chih-Hsin Yang6, Gee-Chen Chang2,7 and Jeremy J.W. Chen1,3,8

1 Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan

2 Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan

3 Agricultural Biotechnology Center, National Chung Hsing University, Taichung, Taiwan

4 Department of Clinical and Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei, Taiwan

5 Graduate Institute of Toxicology, National Taiwan University College of Medicine, Taipei, Taiwan

6 Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

7 Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan

8 Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan

* These two authors contributed equally to this work

Correspondence to:

Jeremy J.W. Chen, email:

Gee-Chen Chang, email:

Keywords: Src, EGFR, lung cancer, rhodomycin A, gefitinib

Received: November 17, 2014 Accepted: June 25, 2015 Published: July 03, 2015

Abstract

Src activation is involved in cancer progression and the interplay with EGFR. Inhibition of Src activity also represses the signalling pathways regulated by EGFR. Therefore, Src has been considered a target molecule for drug development. This study aimed to identify the compounds that target Src to suppress lung cancer tumourigenesis and metastasis and investigate their underlying molecular mechanisms. Using a molecular docking approach and the National Cancer Institute (NCI) compound dataset, eight candidate compounds were selected, and we evaluated their efficacy. Among them, rhodomycin A was the most efficient at reducing the activity and expression of Src in a dose-dependent manner, which was also the case for Src-associated proteins, including EGFR, STAT3, and FAK. Furthermore, rhodomycin A significantly suppressed cancer cell proliferation, migration, invasion, and clonogenicity in vitro and tumour growth in vivo. In addition, rhodomycin A rendered gefitinib-resistant lung adenocarcinoma cells more sensitive to gefitinib treatment, implying a synergistic effect of the combination therapy. Our data also reveal that the inhibitory effect of rhodomycin A on lung cancer progression may act through suppressing the Src-related multiple signalling pathways, including PI3K, JNK, Paxillin, and p130cas. These findings will assist the development of anti-tumour drugs to treat lung cancer.


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