Hehlgans S, Haase M, Cordes N.. Signalling via integrins: implications for cell survival and anticancer strategies. Biochim Biophys Acta 1775: 163-180
OncoRay, Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, University of Technology Dresden, Fetscherstrasse 74/PF 86, 01307 Dresden, Germany. Biochimica et Biophysica Acta
(Impact Factor: 4.66).
02/2007; 1775(1):163-80. DOI: 10.1016/j.bbcan.2006.09.001
Integrin-associated signalling renders cells more resistant to genotoxic anti-cancer agents like ionizing radiation and chemotherapeutic substances, a phenomenon termed cell adhesion-mediated radioresistance/drug resistance (CAM-RR, CAM-DR). Integrins are heterodimeric cell-surface molecules that on one side link the actin cytoskeleton to the cell membrane and on the other side mediate cell-matrix interactions. In addition to their structural functions, integrins mediate signalling from the extracellular space into the cell through integrin-associated signalling and adaptor molecules such as FAK (focal adhesion kinase), ILK (integrin-linked kinase), PINCH (particularly interesting new cysteine-histidine rich protein) and Nck2 (non-catalytic (region of) tyrosine kinase adaptor protein 2). Via these molecules, integrin signalling tightly and cooperatively interacts with receptor tyrosine kinase signalling to regulate survival, proliferation and cell shape as well as polarity, adhesion, migration and differentiation. In tumour cells of diverse origin like breast, colon or skin, the function and regulation of these molecules is partly disturbed and thus might contribute to the malignant phenotype and pre-existent and acquired multidrug resistance. These issues as well as a variety of therapeutic options envisioned to influence tumour cell growth, metastasis and resistance, including kinase inhibitors, anti-integrin antibodies or RNA interference, will be summarized and discussed in this review.
Available from: Nils Cordes
- "Currently, there are 18 α and 8 β subunits known, together forming 24 different receptors with distinct specificity for extracellular matrix (ECM) proteins  . Via recruitment of signaling molecules and adaptor proteins to cytoplasmatic tails of β subunits, integrins contribute to the regulation of cell survival, proliferation, adhesion, motility as well as cancer therapy resistance       . "
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ABSTRACT: Integrin cell adhesion molecules play a crucial role in tumor cell resistance to radio- and chemotherapy and are therefore considered attractive targets for cancer therapy. Here, we assessed the role of β1 integrin-interacting α integrin subunits in more physiological three-dimensional extracellular matrix grown head and neck squamous cell carcinoma (HNSCC) cell cultures for evaluating cytotoxic and radiosensitizing potential. α2, α3, α5 and α6 integrins, which are overexpressed in HNSCC according to Oncomine database analysis, were coprecipitated with β1 integrin. More potently than α2, α5 or α6 integrin inhibition, siRNA-based α3 integrin targeting resulted in reduced clonogenic cell survival, induced apoptosis and enhanced radiosensitivity. These events were associated with diminished phosphorylation of Akt, Cortactin and Paxillin. Cell line-dependently, simultaneous α3 and β1 integrin inhibition led to higher cytotoxicity and radiosensitization than α3 integrin blocking alone. Stable overexpression of wild-type and constitutively active forms of the integrin signaling mediator focal adhesion kinase (FAK) revealed FAK as a key determinant of α3 integrin depletion-mediated radiosensitization. Our findings show that α3 integrin is essentially involved in HNSCC cell radioresistance and critical for a modified cellular radiosensitivity along with β1 integrins.
Copyright © 2014. Published by Elsevier Ireland Ltd.
Available from: Francisco R M Laurindo
- "Focal adhesions are points of interaction between integrins and extracellular matrix (ECM) and draw together adhesion receptors, as well as signaling and cytoskeletal proteins. They are critical to maintaining cellular shape, survival, growth and migration . The focal adhesion kinase is primarily activated during integrin-mediated cell adhesion to ECM and to a lesser extent by growth factors, bioactive lipids, neuropeptides, and ROS . "
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ABSTRACT: Studies have demonstrated that reactive oxygen species (ROS) generated by NADPH oxidase are essential for melanoma proliferation and survival. However, the mechanisms by which NADPH oxidase regulates these effects are still unclear. In this work, we investigate the role of NADPH oxidase-derived ROS in the signaling events that coordinate melanoma cell survival. Using the highly metastatic human melanoma cell line MV3, we observed that pharmacological NADPH oxidase inhibition reduced melanoma viability and induced dramatic cellular shape changes. These effects were accompanied by actin cytoskeleton rearrangement, diminished FAKY397 phosphorylation, and decrease of FAK-actin and FAK-cSrc association, indicating disassembly of focal adhesion processes, a phenomenon that often results in anoikis. Accordingly, NADPH oxidase inhibition also enhanced hypodiploid DNA content, and caspase-3 activation, suggesting activation of the apoptotic machinery. NOX4 is likely to be involved in these effects, since silencing of NOX4 significantly inhibited basal ROS production, reduced FAKY397 phosphorylation and decreased tumor cell viability. Altogether, the results suggest that intracellular ROS generated by the NADPH oxidase, most likely NOX4, transmits cell survival signals on melanoma cells through the FAK pathway, maintaining adhesion contacts and cell viability.
Available from: Ralf Paus
- "Since outside-in signaling via β1 integrin regulates many fundamental epithelial cell functions [6,68], we sought to correlate the observed differences in ORSK outgrowth to proliferation and apoptosis markers. When the dispase-pretreated HF epithelium embedded in the CTS- and BM- mimicking aECM was compared with standard organ-cultured, but also dispase-pretreated HFs, removal of the BM and CTS promoted epithelial cell apoptosis in the human HF epithelium in situ. "
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ABSTRACT: β1 integrin regulates multiple epithelial cell functions by connecting cells with the extracellular matrix (ECM). While β1 integrin-mediated signaling in murine epithelial stem cells is well-studied, its role in human adult epithelial progenitor cells (ePCs) in situ remains to be defined. Using microdissected, organ-cultured human scalp hair follicles (HFs) as a clinically relevant model for studying human ePCs within their natural topobiological habitat, β1 integrin-mediated signaling in ePC biology was explored by β1 integrin siRNA silencing, specific β1 integrin-binding antibodies and pharmacological inhibition of integrin-linked kinase (ILK), a key component of the integrin-induced signaling cascade. β1 integrin knock down reduced keratin 15 (K15) expression as well as the proliferation of outer root sheath keratinocytes (ORSKs). Embedding of HF epithelium into an ECM rich in β1 integrin ligands that mimic the HF mesenchyme significantly enhanced proliferation and migration of ORSKs, while K15 and CD200 gene and protein expression were inhibited. Employing ECM-embedded β1 integrin-activating or -inhibiting antibodies allowed to identify functionally distinct human ePC subpopulations in different compartments of the HF epithelium. The β1 integrin-inhibitory antibody reduced β1 integrin expression in situ and selectively enhanced proliferation of bulge ePCs, while the β1 integrin-stimulating antibody decreased hair matrix keratinocyte apoptosis and enhanced transferrin receptor (CD71) immunoreactivity, a marker of transit amplifying cells, but did not affect bulge ePC proliferation. That the putative ILK inhibitor QLT0267 significantly reduced ORSK migration and proliferation and induced massive ORSK apoptosis suggests a key role for ILK in mediating the ß1 integrin effects. Taken together, these findings demonstrate that ePCs in human HFs require β1 integrin-mediated signaling for survival, adhesion, and migration, and that different human HF ePC subpopulations differ in their response to β1 integrin signaling. These insights may be exploited for cell-based regenerative medicine strategies that employ human HF-derived ePCs.
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