title: 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.affiliation: Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Li
authors.affiliation: Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
authors.forename: Yajie
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China.
authors.forename: Hongbin
authors.initials: H
authors.lastname: Xiao
authors.affiliation: Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Li
authors.affiliation: Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Kan
authors.affiliation: Beijing Hospital of TCM, Capital Medical University, Beijing, 100010, China.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Beijing Hospital of TCM, Capital Medical University, Beijing, 100010, China.
authors.forename: Ganlin
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China.
authors.forename: Zhixin
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
authors.forename: Xiaogang
authors.initials: X
authors.lastname: Weng
authors.affiliation: Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
authors.forename: Bingbing
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
authors.forename: Xucen
authors.initials: X
authors.lastname: Liu
authors.affiliation: Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
authors.forename: Xiaoxin
authors.initials: X
authors.lastname: Zhu
mesh_terms: D000818:Animals; D044946:Biflavonoids / Q000494:pharmacology / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D044946:Biflavonoids; D016212:Transforming Growth Factor beta; C000608934:chamaejasmin B
keywords: Chamaejasmenin B; TGF-β paradox; epithelial-mesenchymal transition; tumor metastasis; tumor microenvironment