Faculty Collaboration Database

Chronic p27^Kip1 Induction by Dexamethasone Causes Senescence Phenotype and Permanent Cell Cycle Blockade in Lung Adenocarcinoma Cells Over-expressing Glucocorticoid Receptor. Sci Rep 2018 Oct 30;8(1):16006

Date

10/31/2018

Pubmed ID

30375484

Pubmed Central ID

PMC6207728

DOI

10.1038/s41598-018-34475-8

Scopus ID

2-s2.0-85055615805 (requires institutional sign-in at Scopus site)   8 Citations

Abstract

Dexamethasone (Dex), co-administered to lung adenocarcinoma patients with pemetrexed chemotherapy, protects against pemetrexed cytotoxicity by inducing reversible G1 arrest, reflected by the effect of Dex on FLT-PET images of patient tumors. However, perioperative Dex treatment increases survival but the mechanism is unknown. In cells with glucocorticoid receptor-α (GR) expression corresponding to higher clinical tumor levels, Dex-induced growth arrest was followed by marked cell expansion, beta-galactosidase expression and Ki67 negativity, despite variable p53 and K-RAS status. Dex induced a transient early surge in p21^Cip1. However, a progressive, irreversible loss of clonogenic growth, whose time of onset was dependent on GR level and Dex dose, was independent of p21^Cip1and caused by gradual accumulation of p27^Kip1 due to transcriptional activation of p27^Kip1 by Dex. This effect was independent of canonical pathways of senescence or p27^Kip1 regulation. The in vitro observations were reflected by growth suppression and P27^Kip1 induction in GR-overexpressing tumor xenografts compared with isogenic low-GR tumors. Extended Dex treatment induces irreversible cell cycle blockade and a senescence phenotype through chronic activation of the p27^Kip1 gene in GR overexpressing lung tumor cell populations and hence could improve outcome of surgery/pemetrexed chemotherapy and sensitize tumors to immunotherapy.

Author List

Patki M, McFall T, Rosati R, Huang Y, Malysa A, Polin L, Fielder A, Wilson MR, Lonardo F, Back J, Li J, Matherly LH, Bepler G, Ratnam M

Author

Thomas Mcfall PhD Assistant Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Cell Cycle Checkpoints
Cell Line, Tumor
Cell Proliferation
Cellular Senescence
Cyclin-Dependent Kinase Inhibitor p27
Dexamethasone
Dose-Response Relationship, Drug
Gene Expression Regulation, Neoplastic
Humans
Immunohistochemistry
Lung Neoplasms
Phenotype
RNA Stability
RNA, Messenger
Receptors, Glucocorticoid