Curcumin Inhibition of the Functional Interaction between Integrin α6β4 and the Epidermal Growth Factor Receptor

The functional interaction between integrin alpha 6 beta 4 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 alpha 6 beta 4 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 alpha 6 beta 4 and the epidermal growth factor receptor (EGFR). In this study, we found that curcumin disrupts functional and physical interactions between alpha 6 beta 4 and EGFR, and blocks alpha 6 beta 4/EGFR-dependent functions of carcinoma cells expressing the signaling competent form of alpha 6 beta 4. We further showed that curcumin inhibits EGF-dependent mobilization of alpha 6 beta 4 from hemidesmosomes to the leading edges of migrating cells such as lammelipodia and filopodia, and thereby prevents alpha 6 beta 4 distribution to lipid rafts where functional interactions between alpha 6 beta 4 and EGFR occur. These data suggest a novel paradigm in which curcumin inhibits alpha 6 beta 4 signaling and functions by altering intracellular localization of alpha 6 beta 4, thus preventing its association with signaling receptors such as EGFR. Mol Cancer Ther; 10(5); 883-91. (C) 2011 AACR.