Salvicine inactivates beta(1) integrin and inhibits adhesion of MDA-MB-435 cells to fibronectin via reactive oxygen species signaling

doi:10.1158/1541-7786.MCR-07-0197

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第一研究室

	Salvicine inactivates beta(1) integrin and inhibits adhesion of MDA-MB-435 cells to fibronectin via reactive oxygen species signaling
	Zhou, Jin; Chen, Yi; Lang, Jing-Yu; Lu, Jin-Jian; Ding, Jian
刊名	MOLECULAR CANCER RESEARCH
	2008-02
卷号	6 期号:2 页码:194-204
ISSN号	1541-7786
DOI	10.1158/1541-7786.MCR-07-0197
文献子类	Article
英文摘要	Integrin-mediated adhesion to the extracellular matrix plays a fundamental role in tumor metastasis. Salvicine, a novel diterpenoid quinone compound identified as a nonintercalative topoisomerase II poison, possesses a broad range of antitumor and antimetastatic activity. Here, the mechanism underlying the antimetastatic capacity of salvicine was investigated by exploring the effect of salvicine on integrin-mediated cell adhesion. Salvicine inhibited the adhesion of human breast cancer MDA-MB-435 cells to fibronectin and collagen without affecting nonspecific adhesion to poly-L-lysine. The fibronectin-dependent formation of focal adhesions and actin stress fibers was also inhibited by salvicine, leading to a rounded cell morphology. Furthermore, salvicine down-regulated beta 1 integrin ligand affinity, clustering and signaling via dephosphorylation of focal adhesion kinase and paxillin. Conversely, salvicine induced extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) phosphorylation. The effect of salvicine on beta 1 integrin function and cell adhesion was reversed by U0126 and SB203580, inhibitors of MAPK/ERK kinase 1/2 and p38 MAPK, respectively. Salvicine also induced the production of reactive oxygen species (ROS) that was reversed by ROS scavenger N-acetyl-L-cysteine. N-acetyl-L-cysteine additionally reversed the salvicine-induced activation of ERK and p38 MAPK, thereby maintaining functional beta 1 integrin activity and restoring cell adhesion and spreading. Together, this study reveals that salvicine activates ERK and p38 MAPK by triggering the generation of ROS, which in turn inhibits beta 1 integrin ligand affinity. These findings contribute to a better understanding of the antimetastatic activity of salvicine and shed new light on the complex roles of ROS and downstream signaling molecules, particularly p38 MAPK, in the regulation of integrin function and cell adhesion.
WOS关键词	OXIDATIVE STRESS ; CARCINOMA-CELLS ; IN-VITRO ; INTEGRIN ACTIVATION ; TOPOISOMERASE-II ; FOCAL ADHESION ; PROTEIN-KINASE ; MAP KINASE ; PATHWAY ; RHO
WOS研究方向	Oncology ; Cell Biology
语种	英语
出版者	AMER ASSOC CANCER RESEARCH
WOS记录号	WOS:000253602800003
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/272999]
专题	药理学第一研究室中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Ding, Jian
作者单位	Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Anti Tumor Pharmacol, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Zhou, Jin,Chen, Yi,Lang, Jing-Yu,et al. Salvicine inactivates beta(1) integrin and inhibits adhesion of MDA-MB-435 cells to fibronectin via reactive oxygen species signaling[J]. MOLECULAR CANCER RESEARCH,2008,6(2):194-204.
APA	Zhou, Jin,Chen, Yi,Lang, Jing-Yu,Lu, Jin-Jian,&Ding, Jian.(2008).Salvicine inactivates beta(1) integrin and inhibits adhesion of MDA-MB-435 cells to fibronectin via reactive oxygen species signaling.MOLECULAR CANCER RESEARCH,6(2),194-204.
MLA	Zhou, Jin,et al."Salvicine inactivates beta(1) integrin and inhibits adhesion of MDA-MB-435 cells to fibronectin via reactive oxygen species signaling".MOLECULAR CANCER RESEARCH 6.2(2008):194-204.