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

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.

• Authors: 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, Xiaoxin Zhu
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 30 Pg. 48180-48192 (Jul 26 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27374079 (Publication Type: Journal Article)

Chemical References

• Biflavonoids
• Transforming Growth Factor beta
• chamaejasmin B

Topics

• Animals
• Biflavonoids (pharmacology, therapeutic use)
• Breast Neoplasms (drug therapy, pathology)
• Disease Models, Animal
• Female
• Humans
• Mammary Neoplasms, Experimental (pathology)
• Mice
• Mice, Inbred BALB C
• Neoplasm Metastasis
• Transforming Growth Factor beta (metabolism)