Zhou Jin, Chen Yi, Lang Jing-Yu, Lu Jin-Jian, Ding Jian
Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, PR China.
Mol Cancer Res. 2008 Feb;6(2):194-204. doi: 10.1158/1541-7786.MCR-07-0197.
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.
整合素介导的与细胞外基质的黏附在肿瘤转移中起关键作用。丹参新醌甲，一种被鉴定为非嵌入性拓扑异构酶II抑制剂的新型二萜醌化合物，具有广泛的抗肿瘤和抗转移活性。在此，通过探究丹参新醌甲对整合素介导的细胞黏附的影响，研究了其抗转移能力的潜在机制。丹参新醌甲抑制人乳腺癌MDA-MB-435细胞与纤连蛋白和胶原蛋白的黏附，而不影响对聚-L-赖氨酸的非特异性黏附。丹参新醌甲还抑制了依赖纤连蛋白的黏着斑和肌动蛋白应力纤维的形成，导致细胞形态变圆。此外，丹参新醌甲通过使黏着斑激酶和桩蛋白去磷酸化，下调β(1)整合素配体亲和力、聚集和信号传导。相反，丹参新醌甲诱导细胞外信号调节激酶(ERK)和p38丝裂原活化蛋白激酶(MAPK)磷酸化。分别用MAPK/ERK激酶1/2和p38 MAPK的抑制剂U0126和SB203580可逆转丹参新醌甲对β(1)整合素功能和细胞黏附的影响。丹参新醌甲还诱导活性氧(ROS)的产生，而ROS清除剂N-乙酰-L-半胱氨酸可逆转这种作用。N-乙酰-L-半胱氨酸还可逆转丹参新醌甲诱导的ERK和p38 MAPK的激活，从而维持功能性β(1)整合素活性，并恢复细胞黏附和铺展。总之，本研究表明丹参新醌甲通过触发ROS的产生来激活ERK和p38 MAPK，进而抑制β(1)整合素配体亲和力。这些发现有助于更好地理解丹参新醌甲的抗转移活性，并为ROS和下游信号分子，特别是p38 MAPK在整合素功能和细胞黏附调节中的复杂作用提供新的线索。
