整合素介導的與細胞外基質的粘附在腫瘤的轉移中起到重要作用。沙爾威辛是一種新型的二萜醌類的非嵌入性拓撲異構酶II毒劑,，具有良好的抗腫瘤和抗轉移作用,。沙爾威辛劑量依賴性地抑制MDA-MB-435細胞與整合素配體纖粘連蛋白（fibronectin）和I型膠原（collagen）的粘附，而對多聚賴氨酸（poly-L-lysine）所介導的非特異性的粘附?jīng)]有影響,。沙爾威辛還可以破壞纖粘連蛋白誘導形成的粘著斑（focal adhesion）和應力纖維,，從而破壞細胞鋪展的形態(tài)，導致細胞變圓,。同時,，沙爾威辛通過對黏著斑激酶和paxillin的去磷酸化下調b1整合素的親和力和聚集。與此同時沙爾威辛激活ERK和p38激酶,，使用U0126和SB203580分別抑制MAPK/ERK1/2和p38的活性可以部分逆轉沙爾威辛對細胞粘附的影響,。沙爾威辛可以誘導活性氧的產(chǎn)生，使用廣譜活性氧抑制劑N-乙酰半胱氨酸可以有效抑制活性氧的產(chǎn)生,，從而抑制ERK和p38的激活,，維持b1整合素的活性并恢復細胞的粘附和鋪展。本研究闡明了沙爾威辛通過促進細胞內ROS生成,，抑制b1整合素的功能,，并下調RhoA的活性破壞細胞微絲骨架，從而抑制細胞與細胞外基質粘附,。這些結果進一步揭示了沙爾威辛抗轉移作用的機制,，此外對于ROS作為一個信號分子在調節(jié)整合素功能和細胞粘附方面也提供了新的內容。研究論文于2008年被作為封面文章發(fā)表于國際癌癥研究權威雜志《分子癌癥研究》（Molecular Cancer Research）上,。（來源：中科院上海藥物研究所）
生物谷推薦原始出處：
（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: [email protected]
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)
