Adhesion to fibronectin via beta 1 integrins regulates p27(kip1) levels and contributes to cell adhesion mediated drug resistance (CAM-DR)

The tumor cell environment may influence drug response through interactions with the extracellular matrix (ECM). We recently reported that adhesion of myeloma cells to fibronectin (FN), via beta 1 integrins is associated with a cell adhesion mediated drug resistance (CAM-DR), Activation of beta 1 in tegrins is known to influence both apoptosis and cell growth. We hypothesiz ed that the FN mediated cytoprotection mag be in part due to perturbations in cell cycle progression. In this report we demonstrate that adhesion of m yeloma cells to FN results in a G(1) arrest associated,vith increased p27(k ip1) protein levels and inhibition of cyclin A and E associated kinase acti vity. Disruption of cells from FN adhesion resulted in a rapid recruitment of cells into S phase, a decrease in p27(kip1) levels, and reversion to a d rug sensitive phenotype. Treatment of cells with p27(Kip1) antisense oligon ucleotides did not affect FN adhesion; however, p27(Kip1) protein levels we re reduced and cells became sensitive to cytotoxic drugs. These studies dem onstrate that beta 1 mediated adhesion of myeloma cells to FN regulates p27 (Kip1) levels and that p27(kip1) levels are causally related to CAM-DR. Dis ruption of beta 1 integrin mediated FN adhesion may represent a potential t arget for the potentiation of drug induced apoptosis.