The Membrane-targeted Alkylphosphocholine Erufosine Interferes with Survival Signals from the Extracellular Matrix
Integrin-dependent adhesion of tumor cells to extracellular matrix proteins provides anchorage-dependent protection from cell
death. In the present investigation we aimed to understand whether and how the paradigmatic membrane-targeted synthetic phospholipid
analog erufosine is relevant for tumor cell adhesion to extracellular matrix proteins, cell survival and migration.
The antineoplastic action of erufosine was analyzed with glioblastoma and prostate cancer cells adhering to fibronectin or collagen I
using proliferation, adhesion and migration assays. The composition of adhesion contacts containing activated β1 integrins was studied
using immunofluorescence. The importance of β1 integrins for the observed effects was analyzed in fibroblasts proficient or deficient in
β1 integrin expression.
Adhesion to collagen I and fibronectin increased the death threshold in serum-deprived tumor cells. Moreover, β1 integrin-deficient cells
were more sensitive to erufosine-treatment compared to β1 integrin proficient cells suggesting a role of β1 integrins for matrix-mediated
death resistance. Most importantly, erufosine disturbed the maturation of the cell adhesion complexes containing paxillin, activated β1
integrins and phosphorylated FAK, leading to a reduction of survival signals and inhibition of tumor cell adhesion and migration. These
findings suggest that membrane-targeted synthetic phospholipids analogs may be of value for counteracting matrix-mediated treatment
resistance in combined treatment approaches with radiotherapy or chemotherapy.
Keywords: Akt, cell death, erufosine, extracellular matrix proteins, β1 integrin, lipid rafts, matrix adhesion, synthetic phospholipids analogs.
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