HUMAN SMALL-CELL LUNG-CANCER CELL-LINES EXPRESSING THE PROOPIOMELANOCORTIN GENE HAVE ABERRANT GLUCOCORTICOID RECEPTOR FUNCTION

Some human small cell lung carcinomas (SCLC) secrete proopiomelanocort in (POMC) derived peptides, but in contrast to the pituitary, glucocor ticoids fail to inhibit this hormone production. We have previously de scribed an in vitro model using human SCLC cell lines that express POM C and are resistant to glucocorticoids. We have now identified the glu cocorticoid receptor (GR) in the SCLC cell line COR L24 using a whole cell ligand binding assay(K-d = 5.7 nM; B-max = 11 fmol/million cells) , while another cell line, DMS 79, lacked significant glucocorticoid b inding. To analyze GR function both positive (GMCO) and negative (TRE) (3)-tkCAT), glucocorticoid-regulated reporter gene constructs were tra nsfected into COR L24 cells. In the SCLC cell line, neither hydrocorti sone nor dexamethasone (500-2,000 nM) significantly induced chloralmph enicol acetyltransferase expression from GMCO; in addition, they did n ot suppress chloramphenicol acetyltransferase expression from (TRE)(3) -tkCAT. Similar results were obtained with two other POMC-expressing S CLC cell lines. Expression of wild type GR in COR L24 cells restored g lucocorticoid signaling, with marked induction of GMCO reporter gene e xpression by dexamethasone (9,100+/-910%; n = 3), and an estimated EC( 50) of 10 nM. This failure of the GR explains the resistance of the PO MC gene to glucocorticoid inhibition and may have implications for cel l growth in SCLC.