title: Vinculin activators target integrins from within the cell to increase melanoma sensitivity to chemotherapy.
abstract: Metastatic melanoma is an aggressive skin disease for which there are no effective therapies. Emerging evidence indicates that melanomas can be sensitized to chemotherapy by increasing integrin function. Current integrin therapies work by targeting the extracellular domain, resulting in complete gains or losses of integrin function that lead to mechanism-based toxicities. An attractive alternative approach is to target proteins, such as vinculin, that associate with the integrin cytoplasmic domains and regulate its ligand-binding properties. Here, we report that a novel reagent, denoted vinculin-activating peptide or VAP, increases integrin activity from within the cell, as measured by elevated (i) numbers of active integrins, (ii) adhesion of cells to extracellular matrix ligands, (iii) numbers of cell-matrix adhesions, and (iv) downstream signaling. These effects are dependent on both integrins and a key regulatory residue A50 in the vinculin head domain. We further show that VAP dramatically increases the sensitivity of melanomas to chemotherapy in clonal growth assays and in vivo mouse models of melanoma. Finally, we show that the increase in chemosensitivity results from increases in DNA damage-induced apoptosis in a p53-dependent manner. Collectively, these findings show that integrin function can be manipulated from within the cell and validate integrins as a new therapeutic target for the treatment of chemoresistant melanomas.
authors: Department of Biochemistry, Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA.
authors: Elke S
authors: ES
authors: Nelson
authors: Andrew W
authors: AW
authors: Folkmann
authors: Michael D
authors: MD
authors: Henry
authors: Kris A
authors: KA
authors: DeMali
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001426:Bacterial Proteins / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005347:Fibroblasts / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D010446:Peptide Fragments / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D016596:Vinculin / Q000819:agonists*
chemical_list: D000970:Antineoplastic Agents; D001426:Bacterial Proteins; D016023:Integrins; D010446:Peptide Fragments; C561878:vinculin-activating peptide, Shigella flexneri; D016596:Vinculin