整合素介导的与细胞外基质的粘附在肿瘤的转移中起到重要作用。沙尔威辛是一种新型的二萜醌类的非嵌入性拓扑异构酶II毒剂，具有良好的抗肿瘤和抗转移作用。沙尔威辛剂量依赖性地抑制MDA-MB-435细胞与整合素配体纤粘连蛋白（fibronectin）和I型胶原（collagen）的粘附，而对多聚赖氨酸（poly-L-lysine）所介导的非特异性的粘附没有影响。沙尔威辛还可以破坏纤粘连蛋白诱导形成的粘着斑（focal adhesion）和应力纤维，从而破坏细胞铺展的形态，导致细胞变圆。同时，沙尔威辛通过对黏着斑激酶和paxillin的去磷酸化下调b1整合素的亲和力和聚集。与此同时沙尔威辛激活ERK和p38激酶，使用U0126和SB203580分别抑制MAPK/ERK1/2和p38的活性可以部分逆转沙尔威辛对细胞粘附的影响。沙尔威辛可以诱导活性氧的产生，使用广谱活性氧抑制剂N-乙酰半胱氨酸可以有效抑制活性氧的产生，从而抑制ERK和p38的激活，维持b1整合素的活性并恢复细胞的粘附和铺展。本研究阐明了沙尔威辛通过促进细胞内ROS生成，抑制b1整合素的功能，并下调RhoA的活性破坏细胞微丝骨架，从而抑制细胞与细胞外基质粘附。这些结果进一步揭示了沙尔威辛抗转移作用的机制，此外对于ROS作为一个信号分子在调节整合素功能和细胞粘附方面也提供了新的内容。研究论文于2008年被作为封面文章发表于国际癌症研究权威杂志《分子癌症研究》（Molecular Cancer Research）上。（来源：中科院上海药物研究所）
生物谷推荐原始出处：
（Molecular Cancer Research ），6, 194-204, February 1, 2008，Jin Zhou，Jian Ding
Salvicine Inactivates β1 Integrin and Inhibits Adhesion of MDA-MB-435 Cells to Fibronectin via Reactive Oxygen Species Signaling
Jin Zhou, Yi Chen, Jing-Yu Lang, Jin-Jian Lu and Jian Ding
Requests for reprints: Jian Ding, Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhangjiang Hi-Tech Park, Shanghai 201203, People's Republic of China. Phone: 86-21-50806722; Fax: 86-21-50806722. E-mail: jding@mail.shcnc.ac.cn
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 β1 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 β1 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 β1 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 β1 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. (Mol Cancer Res 2008;6(2):194–204)
