Huang Qing, Shen Han-Ming, Shui Guanghou, Wenk Markus R, Ong Choon-Nam
Department of Community, Occupational, and Family Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Cancer Res. 2006 Jun 1;66(11):5807-15. doi: 10.1158/0008-5472.CAN-06-0077.
Cell adhesion and spreading is a crucial step in the metastatic cascade of cancer cells, and interruption of this step is considered to be a logical strategy for prevention and treatment of tumor metastasis. Emodin is the major active component of the rhizome of Rheum palmatum L., with known anticancer activities. Here, we first found that emodin significantly inhibited cell adhesion of various human cancer cells. This inhibition was achieved through suppressing the recruitment of focal adhesion kinase (FAK) to integrin beta(1) as well as the phosphorylation of FAK followed by the decreased formation of focal adhesion complex (FAC). In understanding the underlying mechanisms, we found that emodin inhibited the lipid raft clustering and subsequent colocalization of integrin beta(1) and FAC proteins within lipid rafts. Lipid profile analysis revealed significant decrease of cholesterol and sphingolipids in raft fraction after emodin treatment. Cholesterol replenishment abolished the adverse effect of emodin on the translocation of integrin beta(1) and FAC proteins into the lipid raft fraction and cell adhesion. Therefore, data from this study provide novel evidence that emodin inhibits cell adhesion and spreading through disruption of the membrane lipid raft-associated integrin signaling pathway.
细胞黏附和铺展是癌细胞转移级联反应中的关键步骤，而阻断这一步骤被认为是预防和治疗肿瘤转移的合理策略。大黄素是掌叶大黄根茎的主要活性成分，具有已知的抗癌活性。在此，我们首次发现大黄素能显著抑制多种人类癌细胞的细胞黏附。这种抑制作用是通过抑制黏着斑激酶（FAK）向整合素β1的募集以及FAK的磷酸化，进而减少黏着斑复合物（FAC）的形成来实现的。在探究其潜在机制时，我们发现大黄素抑制脂筏聚集以及整合素β1和FAC蛋白随后在脂筏内的共定位。脂质谱分析显示，大黄素处理后脂筏组分中的胆固醇和鞘脂显著减少。胆固醇补充消除了大黄素对整合素β1和FAC蛋白向脂筏组分转位及细胞黏附的不利影响。因此，本研究的数据提供了新的证据，表明大黄素通过破坏膜脂筏相关的整合素信号通路来抑制细胞黏附和铺展。
