Abstract 4809: Targeting integrin function in melanoma cells using vinculin activators results in enhances chemosensitivity

Abstract

Abstract Current therapies aimed at manipulating cell adhesion work by modulating interactions between integrins (the major adhesion receptors on the cell surface) and components of the extracellular matrix. However, a complete gain or loss of integrin function can lead to mechanism-based toxicities. An attractive alternative approach is to manipulate integrin-associated proteins. Vinculin, an actin binding protein that is recruited to the cytoplasmic tail of integrin β1, is a good candidate protein for such an approach, as it regulates the strength and lifetime of such complexes. Here we have investigated the effect that a vinculin activating peptide (VAP) has on integrin-mediated adhesion. In HeLa cells and mouse embryonic fibroblasts, VAP increased integrin-mediated signaling, as well as adhesion to fibronectin and collagen, in an integrin- and vinculin-dependent manner. These regulatory effects of VAP were dependent on the peptide's ability to bind to an amphipathic α-helix in the vinculin head; substitution of an isoleucine for alanine at position 50 within this region of vinculin abolished VAP's ability to enhance adhesion. In melanoma cells, VAP likewise increased integrin-mediated cell adhesion, and increased the cells’ sensitivity to cancer chemotherapeutics, suggesting that it might serve as an effective therapeutic agent. Overall, our findings demonstrate that integrin function can be manipulated by targeting the regulation of proteins that associate with the cytoplasmic domains of the integrins, and suggest that small molecules capable of such regulation may be employed as effective adjuvants to chemotherapy for melanoma. These findings lay the foundation for the development of a new class of therapeutics that act by regulating integrin-associated proteins. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4809.