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Glucocorticoids Inhibit Lung Cancer Cell Growth through Both the Extracellular Signal-Related Kinase Pathway and Cell Cycle Regulators

Departments of Medicine, Biochemistry, Pathology, and Environmental Medicine, Division of Pulmonary and Critical Care Medicine, New York University School of Medicine; and the Kaplan Comprehensive Cancer Center, New York University School of Medicine, New York, New York

Address correspondence to: Alissa K. Greenberg, M.D., Division of Pulmonary and Critical Care Medicine, Department of Medicine, New York University School of Medicine, 550 First Avenue, Rm. NB-7N24, New York, NY 10016. E-mail: alissa.greenberg{at}med.nyu.edu

Glucocorticoids inhibit the proliferation of various cell types, but the mechanism of this inhibition remains unclear. We investigated the effect of dexamethasone on non–small cell lung cancer cell growth and cell cycle progression. We showed that dexamethasone suppresses the proliferation of A549 and Calu-1 cells, with accumulation of cells in G1/G0 stage of the cell cycle, as determined by fluorescence-activated cell sorter analysis. Western blot analysis confirmed that this is associated with hypophosphorylation of retinoblastoma protein. Using Western blot analysis and in vitro kinase assays, we found that dexamethasone results in decreased activity of CDK2 and 4, decreased levels of cyclin D, E2F, and Myc, and increased levels of the CDK inhibitor p21^Cip1. In addition, we found that dexamethasone decreases activity of extracellular signal-related kinase (ERK)/mitogen-activated protein kinase (MAPK). The kinetics of all these changes indicate that inhibition of the ERK/MAPK pathway precedes the cell cycle effects, suggesting that regulation of this MAPK-signaling pathway may be an alternative mechanism for glucocorticoid-induced cell cycle arrest and growth inhibition.

Abbreviations: cyclin-dependent kinase, CDK • CDK inhibitors, CKI • enhanced chemiluminescence, ECL • extracellular signal-related kinases, ERK • fluorescence-activated cell sorter, FACS • glucocorticoid receptor, GR • glucocorticoid response element, GRE • mitogen-activated protein kinase, MAPK • MAPK phosphatase, MKP • phosphate-buffered saline, PBS

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