Dw. Ray et al., GLUCOCORTICOID RECEPTOR STRUCTURE AND FUNCTION IN GLUCOCORTICOID-RESISTANT SMALL-CELL LUNG-CARCINOMA CELLS, Cancer research, 56(14), 1996, pp. 3276-3280
Human small cell lung carcinomas (SCLCs) frequently express the adreno
corticotrophin precursor gene proopiomelanocortin. Glucocorticoids usu
ally fail to inhibit this ectopic adrenocorticotrophin production, in
contrast to their effects in the pituitary. We have shown three human
SCLC cell lines to be globally resistant to glucocorticoid action; in
two of these lines this occurs despite the presence of glucocorticoid
receptors (GR+), Accordingly, we have cloned and sequenced the GR codi
ng region from one of these two GR+, SCLC cell lines, COR L24, and ide
ntified compound heterozygous mutations. One allele had a single nucle
otide substitution of A to G in the NH2-terminal domain, which altered
Asp to Ser at amino acid 363. The other allele contained a trinucleot
ide insertion at the 5' boundary of exon 4, which introduced an additi
onal amino acid, Arg(453), between the two zinc fingers of the DNA bin
ding domain. In cotransfection studies using the glucocorticoid respon
sive mouse mammary tumor virus-luciferase Ser(363) did not alter recep
tor function. In contrast, Arg(453) encoded a GR with 48% V-max activi
ty compared to wild-type receptor (P < 0.001), with an unchanged EC(50
). Thus, GR mutations may contribute to the glucocorticoid-resistant p
henotype of GR+ COR L24 cells, which could confer survival advantage t
o this highly malignant neuroendocrine tumor.