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Adhesion to fibronectin via β1 integrins regulates p27kip1 levels and contributes to cell adhesion mediated drug resistance (CAM-DR)

Oncogene volume 19, pages 4319–4327 (2000)Cite this article

Abstract

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 β1 integrins is associated with a cell adhesion mediated drug resistance (CAM-DR). Activation of β1 integrins is known to influence both apoptosis and cell growth. We hypothesized that the FN mediated cytoprotection may 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 G1 arrest associated with increased p27kip1 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 p27kip1 levels, and reversion to a drug sensitive phenotype. Treatment of cells with p27Kip1 antisense oligonucleotides did not affect FN adhesion; however, p27Kip1 protein levels were reduced and cells became sensitive to cytotoxic drugs. These studies demonstrate that β1 mediated adhesion of myeloma cells to FN regulates p27kip1 levels and that p27kip1 levels are causally related to CAM-DR. Disruption of β1 integrin mediated FN adhesion may represent a potential target for the potentiation of drug induced apoptosis.

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Acknowledgements

Peggy Farrell for careful editing of the manuscript. This work was funded by CA 83765 (WSD) and CA 72694 (WJP). Flow Cytometry Core Facility at H. Lee Moffitt Cancer Center CA 76292. LA Hazlehurst is funded in part by a Kathy Guisti Multiple Myeloma Research Foundation Grant.

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Authors and Affiliations

  1. Department of Oncology and Clinical Investigation Program, University of South Florida Tampa, 33612, Florida, FL, USA

    L A Hazlehurst, J S Damiano, I Buyuksal & W S Dalton

  2. Department of Biochemistry and Molecular Biology, University of South Florida, Tampa, 33612, Florida, FL, USA

    W J Pledger & W S Dalton

  3. H Lee Moffitt Cancer Center and Research Institute, University of South Florida, 12902 Magnolia Drive, Tampa, 33612, Florida, FL, USA

    L A Hazlehurst, J S Damiano, I Buyuksal, W J Pledger & W S Dalton

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Hazlehurst, L., Damiano, J., Buyuksal, I. et al. Adhesion to fibronectin via β1 integrins regulates p27kip1 levels and contributes to cell adhesion mediated drug resistance (CAM-DR). Oncogene 19, 4319–4327 (2000). https://doi.org/10.1038/sj.onc.1203782

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