Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71103, USA.
Mol Cancer Ther. 2011 May;10(5):883-91. doi: 10.1158/1535-7163.MCT-10-1053. Epub 2011 Mar 9.
The functional interaction between integrin α6β4 and growth factor receptors has been implicated in key signaling pathways important for cancer cell function. However, few attempts have been made to selectively target this interaction for therapeutic intervention. Previous studies showed that curcumin, a yellow pigment isolated from turmeric, inhibits integrin α6β4 signaling important for breast carcinoma cell motility and invasion, but the mechanism is not currently known. To address this issue, we tested the hypothesis that curcumin inhibits the functional interaction between α6β4 and the epidermal growth factor receptor (EGFR). In this study, we found that curcumin disrupts functional and physical interactions between α6β4 and EGFR, and blocks α6β4/EGFR-dependent functions of carcinoma cells expressing the signaling competent form of α6β4. We further showed that curcumin inhibits EGF-dependent mobilization of α6β4 from hemidesmosomes to the leading edges of migrating cells such as lammelipodia and filopodia, and thereby prevents α6β4 distribution to lipid rafts where functional interactions between α6β4 and EGFR occur. These data suggest a novel paradigm in which curcumin inhibits α6β4 signaling and functions by altering intracellular localization of α6β4, thus preventing its association with signaling receptors such as EGFR.
整合素 α6β4 与生长因子受体的功能相互作用已被牵涉到对癌细胞功能至关重要的关键信号通路中。然而，很少有尝试被用于选择性地靶向这种相互作用以进行治疗干预。先前的研究表明，姜黄素，一种从姜黄中分离出来的黄色色素，可抑制整合素 α6β4 信号，这对乳腺癌细胞的迁移和侵袭很重要，但目前尚不清楚其机制。为了解决这个问题，我们检验了这样一个假设，即姜黄素抑制α6β4 与表皮生长因子受体（EGFR）之间的功能相互作用。在这项研究中，我们发现姜黄素破坏了 α6β4 和 EGFR 之间的功能和物理相互作用，并阻断了表达信号功能形式的 α6β4 的癌细胞中 α6β4/EGFR 依赖性功能。我们进一步表明，姜黄素抑制 EGF 依赖性将 α6β4 从粘着斑迁移到迁移细胞的前缘，如片状伪足和丝状伪足，从而防止 α6β4 分布到脂质筏，其中发生 α6β4 与 EGFR 之间的功能相互作用。这些数据表明了一个新的范例，即姜黄素通过改变 α6β4 的细胞内定位来抑制 α6β4 信号和功能，从而防止其与信号受体（如 EGFR）的关联。
