Oncotarget

Research Papers:

Chamaejasmenin B, a novel candidate, inhibits breast tumor metastasis by rebalancing TGF-beta paradox

Qi Li, Yajie Wang, Hongbin Xiao, Yujie Li, Xiaoxi Kan, Xiaomin Wang, Ganlin Zhang, Zhixin Wang, Qing Yang, Xi Chen, Xiaogang Weng, Ying Chen, Bingbing Zhou, Yan Guo, Xucen Liu and Xiaoxin Zhu _

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Oncotarget. 2016; 7:48180-48192. https://doi.org/10.18632/oncotarget.10193

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Abstract

Qi Li1, Yajie Wang1, Hongbin Xiao3, Yujie Li1, Xiaoxi Kan1, Xiaomin Wang2, Ganlin Zhang2, Zhixin Wang3, Qing Yang1, Xi Chen1, Xiaogang Weng1, Ying Chen1, Bingbing Zhou1, Yan Guo1, Xucen Liu1, Xiaoxin Zhu1

1Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China

2Beijing Hospital of TCM, Capital Medical University, Beijing, 100010, China

3Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China

Correspondence to:

Xiaoxin Zhu, email: [email protected]

Keywords: Chamaejasmenin B, tumor metastasis, TGF-β paradox, epithelial-mesenchymal transition, tumor microenvironment

Abbreviations: EMT, Epithelial-Mesenchymal Transition, ESC, Extract from Stellera chamaejasme L, ICJ, Chamaejasmenin B, Stellera chamaejasme L, SCL

Received: October 28, 2015    Accepted: June 07, 2016    Published: June 21, 2016

ABSTRACT

Metastasis is the leading lethal factor severely restraining the effectiveness of clinical treatment. TGF-beta is the key regulator for metastasis and influences paradoxically on cancer progression. The known TGF-beta blockers exert little selectivity on its functions, indiscriminately causing the anti-metastatic and pro-growth effects. Under such circumstances, specifically rebalancing the oncological function of TGF-beta provides a crucial oncotarget against metastasis. In our study, we established the screening platform targeting cell motility and identified a potential flavonoid, Chamaejasmenin B (ICJ), extracted from Stellera chamaejasme L..It suppressed the migration and invasion in breast cancer cells in vitro. Moreover, by dynamical quantification of breast cancer progression in small-animal imaging system, ICJ was proved to be a potent inhibitor of metastasis with minimal toxic side effects. Mechanism study further revealed that ICJ efficiently blocked TGF-beta induced EMT, disrupted the interaction between β3 integrin-TβRII complex and, consequently, resulted in the selective inhibition of FAK:Src:p38 pathway. Meanwhile, specific blockage of this pathway largely attenuated the anti-metastatic function of ICJ. Importantly, in contrast with the antagonistic effects on TGF-beta induced metastasis, ICJ obviously sensitized its cytostatic activity, suggesting that it was not a pan-blocker but a rebalancer for the functional output of TGF-beta. Collectively, by targeting TGF-beta Paradox, we experimentally provided a promising candidate for metastatic intervention.


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