Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2006) 11 P763

ECE2006 Poster Presentations Steroids (44 abstracts)

Glucocorticoid receptors exert a profound anti-proliferative and anti-survival effect on human small cell lung cancer cells

P Le Rouzic , H Gillingham , A Berry , M Kayahara , T Huynh , P Sommer , A White & DW Ray


University of Manchester, Manchester, United Kingdom.


Glucocorticoids (Gcs) act via the glucocorticoid receptor (GR) to inhibit proliferation of many epithelial cell types, and induce apoptosis in others, notably lymphoblastic leukemia. Resistance to Gcs occurs in human small cell lung cancer (SCLC), manifest clinically as dysregulated secretion of ACTH-related peptides. Currently nothing is known of the biological consequences such resistance causes. We have previously shown that a panel of human SCLC cell lines secrete ACTH related peptides, and are globally resistant to glucocorticoid action. These cell lines are a tractable model for a major, rapidly lethal human disease.

Overexpression of wild-type GR restores Gc sensitivity to transfected reporter genes in the SCLC cells. Therefore we analysed the effects of such restoration of Gc action on cell phenotype. Initial studies used classical stable transfection, and revealed three striking findings. Transfected cells proliferated more slowly, ACTH peptide secretion was inhibited by Gcs, and Gc sensitivity was rapidly lost. To generate sufficient cell numbers for comprehensive analysis, the SCLC cells were subject to retroviral infection with GR-EYFP expression constructs. The retroviruses conferred glucocorticoid sensitivity to another Gc resistant human cell line, HEK293, with appropriate nuclear translocation, GR phosphorylation, and regulation of both endogenous and transfected reporter genes. The retroviruses similarly conferred Gc sensitivity to two different Gc resistant SCLC cell lines. However, in these cells, expression of GR caused massive cell loss with 80% of GR expressing cells appearing apoptotic, compared to cells infected with a control virus.

We show, for the first time, a profound anti-survival effect of GR expression on human small cell lung cancer. Therefore evasion of Gc signalling, confers a survival advantage to the cells. Understanding how glucocorticoids work in SCLC may lead to novel therapeutic approaches.

Volume 11

8th European Congress of Endocrinology incorporating the British Endocrine Societies

European Society of Endocrinology 
British Endocrine Societies 

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