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

Abstract

The functional interaction between integrin a6b4 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 a6b4 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 a6b4 and the epidermal growth factor receptor (EGFR). In this study, we found that curcumin disrupts functional and physical interactions between a6b4 and EGFR, and blocks a6b4/EGFR-dependent functions of carcinoma cells expressing the signaling competent form of a6b4. We further showed that curcumin inhibits EGF-dependent mobilization of a6b4 from hemidesmosomes to the leading edges of migrating cells such as lammelipodia and filopodia, and thereby prevents a6b4 distribution to lipid rafts where functional interactions between a6b4 and EGFR occur. These data suggest a novel paradigm in which curcumin inhibits a6b4 signaling and functions by altering intracellular localization of a6b4, thus preventing its association with signaling receptors such as EGFR. Mol Cancer Ther; 10(5); 883-91. Ó2011 AACR.

The Molecular Basis for the Pharmacokinetics and Pharmacodynamics of Curcumin and Its Metabolites in Relation to Cancer

“…uPA levels were also decreased in curcumin-treated cells, in which inhibition of NF-kB activity was identified as the chief culprit . Similarly, inhibition of tumor metastasis by curcumin has been frequently observed and attributed to the reduction in MMP-2, MMP-9, uPA, and aquaporin 3 protein levels Weissenberger et al, 2010;Wong et al, 2010;Soung and Chung, 2011). Although the mechanism is relatively elusive, aquaporins play a role in tumor growth and metastasis (Nico and Ribatti, 2010), during which MMPs are upregulated via the PI3K-Akt pathway to facilitate these processes.…”

Clinical significance of the integrin α6β4 in human malignancies

“…Notably, cooperative signaling has been identified between integrin α6β4 and multiple members of the EGFR family. EGFR and integrin α6β4 have also been shown to co-localize at the leading edge of carcinoma cells subjected to EGF stimulation, and their interaction was inhibited by curcumin, a compound present in turmeric (48). Integrin α6β4 has also been shown to associate with ErbB-2 in multiple breast carcinoma cell lines (30, 49), though reports are conflicting as to whether integrin α6β4 expression correlates with ErbB-2 protein overexpression in patient-derived carcinoma tissues (50–53).…”

Progress toward Understanding Protein S-acylation: Prospective in Plants

“…It was reported that S-acylation of metastasis-associated proteins KAT1/CD82, CD9, and CD151 is essential for their function of suppressing metastasis or inhibiting tumor cell adhesion and migration (Zhou et al, 2004; Hemler, 2014; Termini et al, 2014). Integrin β4 (ITGβ4) can interact with growth factor receptors and enhance invasive potential of cancer cells (Soung and Chung, 2011). This is helped by the S-acylation of ITGβ4 which is required for its lipid raft localization in the membrane and signaling activity.…”