Signalling via integrins: implications for cell survival and anticancer strategies.
ABSTRACT 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.
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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.Cancer Letters 12/2014; 357(2). · 5.02 Impact Factor