Biochem Pharmacol 2011 Dec;82 (12): 1873-83. [IF:4.889]
Gambogic acid inhibits tumor cell adhesion by suppressing integrin β1 and membrane lipid rafts-associated integrin signaling pathway.
Li C , Lu N , Qi Q , Li F , Ling Y , Chen Y , Qin Y , Li Z , Zhang H , You Q , Guo Q .
Jiangsu Key Laboratory of Carcinogenesis and Intervention (China Pharmaceutical University), Tongjiaxiang 24, Nanjing 210009, People's Republic of China.
中国药科大学江苏省肿瘤发生与干预重点实验室
Abstract
Cell adhesion plays an important role in the steps of cancer metastasis. Regulation of cell-cell (intercellular) and cell-matrix adhesion is a promising strategy for cancer progression. Gambogic acid is a xanthone derived from the resin of the Chinese plant Garciania hanburyi, with potent anti-metastasis activity on highly metastatic cells. The aim of this study was to investigate the function and mechanism of gambogic acid on tumor adhesion. We found that gambogic acid strongly inhibited the adhesion of human cancer cells to fibronectin. This inhibition was associated with the deformation of focal adhesion complex, which was mediated by suppressing the expression of integrin β1 and integrin signaling pathway. In vitro, cell lipid rafts clustering was inhibited following treatment of gambogic acid, which induced the suppression of integrin β1 and focal adhesion complex proteins colocalization within rafts. Moreover, gambogic acid significantly decreased cellular cholesterol content, whereas cholesterol replenishment lessened the inhibitory effect of gambogic acid on cell adhesion. Real-time PCR analysis showed that gambogic acid reduced mRNA levels of hydroxymethylglutaryl-CoA reductase and sterol regulatory element binding protein-2, while increased acetyl-CoA acetyltransferase-1/2. Taken together, these results demonstrate that gambogic acid inhibits cell adhesion via suppressing integrin β1 abundance and cholesterol content as well as the membrane lipid raft-associated integrin function, which provide new evidence for the anti-cancer activity of gambogic acid.
摘要：
细胞粘附在癌细胞转移的过程中起着重要的作用，调控细胞与细胞（间）及细胞与外基质间的粘附对癌症的发展是一个很有前途的策略。藤黄酸是源自中国植物Garciania hanburyi的一种口山酮类衍生物，对高转移性细胞具有潜在的抗转移活性。本研究的目的在于探讨藤黄酸对肿瘤粘连的功能和机制。我们发现，藤黄酸可强烈抑制人类癌细胞对纤维连接蛋白的粘附，这种抑制作用伴随着粘着复合物的变形，是通过抑制整合素β1的表达和整合信号通路来介导的。在体外，经藤黄酸处理后细胞脂质筏聚类受到抑制，从而诱发整合素β1的抑制及粘着复合蛋白与细胞脂质筏的共存。此外，藤黄酸可显著降低细胞内胆固醇含量，而胆固醇的不充足减轻了藤黄酸对细胞粘附的抑制作用。实时PCR分析表明，藤黄酸可减少羟甲基-CoA还原酶和固醇调节元件结合蛋白-2的mRNA水平，而增加乙酰辅酶A乙酰转移酶-1/2的mRNA水平。综合考虑，这些结果表明藤黄酸通过抑制整合素β1的丰度和胆固醇含量以及细胞膜脂质筏相关的整合功能来抑制细胞粘附的，这为藤黄酸的抗肿瘤活性提供了新的证据。
