Human small cell lung cancer cell lines expressing the proopiomelanocortin gene have aberrant glucocorticoid receptor function.
Some human small cell lung carcinomas (SCLC) secrete proopiomelanocortin (POMC) derived peptides, but in contrast to the pituitary, glucocorticoids fail to inhibit this hormone production. We have previously described an in vitro model using human SCLC cell lines that express POMC and are resistant to glucocorticoids. We have now identified the glucocorticoid receptor (GR) in the SCLC cell line COR L24 using a whole cell ligand binding assay (Kd = 5.7 nM; Bmax = 11 fmol/million cells), while another cell line, DMS 79, lacked significant glucocorticoid binding. To analyze GR function both positive (GMCO) and negative (TRE)3-tkCAT), glucocorticoid-regulated reporter gene constructs were transfected into COR L24 cells. In the SCLC cell line, neither hydrocortisone nor dexamethasone (500-2,000 nM) significantly induced chloramphenicol acetyltransferase expression from GMCO; in addition, they did not suppress chloramphenicol acetyltransferase expression from (TRE)3-tkCAT. Similar results were obtained with two other POMC-expressing SCLC cell lines. Expression of wild type GR in COR L24 cells restored glucocorticoid signaling, with marked induction of GMCO reporter gene expression by dexamethasone (9,100 +/- 910%; n = 3), and an estimated EC50 of 10 nM. This failure of the GR explains the resistance of the POMC gene to glucocorticoid inhibition and may have implications for cell growth in SCLC.
Ray
D W
DW
Department of Medicine, University of Manchester, United Kingdom.
Littlewood
A C
AC
Clark
A J
AJ
Davis
J R
JR
White
A
A
D018288:Carcinoma, Small Cell / Q000378:metabolism* / Q000473:pathology; D015870:Gene Expression; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D011333:Pro-Opiomelanocortin / Q000235:genetics*; D011965:Receptors, Glucocorticoid / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured
D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D011333:Pro-Opiomelanocortin