Adhesion to fibronectin via β1 integrins regulates p27kip1 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 integrins is known to influence both apoptosis and cell growth. We hypothesized that the FN mediated cytoprotection mag be in part due to perturbations in cell cycle progression. In this report we demonstrate that adhesion of myeloma cells to FN results in a G(1) arrest associated,vith increased p27(kip1) protein levels and inhibition of cyclin A and E associated kinase activity. 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 drug sensitive phenotype. Treatment of cells with p27(Kip1) antisense oligonucleotides did not affect FN adhesion; however, p27(Kip1) protein levels were reduced and cells became sensitive to cytotoxic drugs. These studies demonstrate 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. Disruption of beta 1 integrin mediated FN adhesion may represent a potential target for the potentiation of drug induced apoptosis.