Journal article
Vinculin activators target integrins from within the cell to increase melanoma sensitivity to chemotherapy
Molecular cancer research, Vol.9(6), pp.712-723
06/2011
DOI: 10.1158/1541-7786.MCR-10-0599
PMCID: PMC3134390
PMID: 21460181
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: (1) numbers of active integrins, (2) adhesion of cells to extracellular matrix ligands, (3) numbers of cell-matrix adhesions, and (4) 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 demonstrate that the increase in chemosensitivity results from increases in DNA damage-induced apoptosis in a p53-dependent manner. Collectively these findings demonstrate for the first time that integrin function can be manipulated from within the cell and validate integrins as a new therapeutic target for the treatment of chemoresistant melanomas.
Details
- Title: Subtitle
- Vinculin activators target integrins from within the cell to increase melanoma sensitivity to chemotherapy
- Creators
- Elke S Nelson - Department of Biochemistry, Roy J. and Lucille A. Carver College of Medicine; 51 Newton Rd. Iowa City, IA 52242Andrew W Folkmann - Department of Biochemistry, Roy J. and Lucille A. Carver College of Medicine; 51 Newton Rd. Iowa City, IA 52242Michael D Henry - Department of Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine; 51 Newton Rd. Iowa City, IA 52242Kris A DeMali - Department of Biochemistry, Roy J. and Lucille A. Carver College of Medicine; 51 Newton Rd. Iowa City, IA 52242
- Resource Type
- Journal article
- Publication Details
- Molecular cancer research, Vol.9(6), pp.712-723
- DOI
- 10.1158/1541-7786.MCR-10-0599
- PMID
- 21460181
- PMCID
- PMC3134390
- ISSN
- 1541-7786
- eISSN
- 1557-3125
- Language
- English
- Date published
- 06/2011
- Academic Unit
- Dermatology; Molecular Physiology and Biophysics; Pathology; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Urology
- Record Identifier
- 9984024409502771
Metrics
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