Glucocorticoids inhibit lung cancer cell growth through both the extracellular signal-related kinase pathway and cell cycle regulators.
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.
Greenberg
Alissa K
AK
Department of Medicine, New York University School of Medicine, New York 10016, USA. alissa.greenberg@med.nyu.edu
Hu
Jing
J
Basu
Sharmila
S
Hay
John
J
Reibman
Joan
J
Yie
Ting-An
TA
Tchou-Wong
Kam Meng
KM
Rom
William N
WN
Lee
Theodore C
TC
D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects; D056741:Cyclin D; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000187:drug effects / Q000378:metabolism*; D016213:Cyclins / Q000187:drug effects / Q000378:metabolism; D004268:DNA-Binding Proteins; D003907:Dexamethasone / Q000494:pharmacology; D050684:E2F Transcription Factors; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D010766:Phosphorylation; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000187:drug effects / Q000378:metabolism; D014157:Transcription Factors; D014407:Tumor Cells, Cultured
C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D056741:Cyclin D; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D016160:Retinoblastoma Protein; D014157:Transcription Factors; D003907:Dexamethasone; D018844:Cyclin-Dependent Kinases