ausblenden:
Schlagwörter:
INTEGRIN-MEDIATED ADHESION; LIPID RAFTS; CANCER CELLS; ANTICANCER
ALKYLPHOSPHOLIPIDS; IONIZING-RADIATION; MULTIPLE-MYELOMA; GENOTOXIC
INJURY; PROSTATE-CANCER; DOWN-REGULATION; PI3K PATHWAYAkt; cell death; erufosine; extracellular matrix proteins; beta 1
integrin; lipid rafts; matrix adhesion; synthetic phospholipids analogs;
Zusammenfassung:
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 beta 1 integrins was studied using immunofluorescence. The importance of beta 1 integrins for the observed effects was analyzed in fibroblasts proficient or deficient in beta 1 integrin expression.
Adhesion to collagen I and fibronectin increased the death threshold in serum-deprived tumor cells. Moreover, beta 1 integrin-deficient cells were more sensitive to erufosine-treatment compared to beta 1 integrin proficient cells suggesting a role of beta 1 integrins for matrix-mediated death resistance. Most importantly, erufosine disturbed the maturation of the cell adhesion complexes containing paxillin, activated beta 1 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.
