Small cell lung cancer (SCLC) is an aggressive disease with a poor prognosis. 
These cancers are deficient in glucocorticoid receptor (GR) expression, and 
therefore, resistant to glucocorticoids. Overexpression of the GR both in vivo 
and in vitro leads to apoptotic cell death suggesting that loss of GR is 
favorable for cancer growth. Indeed, the GR promoter is silenced in SCLC cells 
by methylation. We now show that treatment of the SCLC cell line (DMS79) cells 
with the demethylating agent, 5-aza-2'-deoxycytidine (5-aza), results in 
significant endogenous re-expression of both GRα and the ligand-independent 
GR-P. The GR gene has a complex promoter region comprising nine alternative 
promoters, the proximal seven of which lie within a CpG island. The endogenous 
re-expression seen is attributed to the constitutive promoters 1B and 1C and 1J 
but predominantly 1F, which we show to be heavily methylated in SCLC cells. Flow 
cytometric analysis using the apoptotic marker, Annexin V, shows that this 
endogenous re-expression is sufficient to drive the SCLC cells to apoptosis. 
Apoptotic induction is specific to GR re-expression as cotreatment with 5-aza 
and the GR antagonist, RU486 prevented apoptosis. Of the three functional GR 
domains (the DNA binding domain, ligand binding domain, and transactivation 
domain), we identified that the transactivation domain is essential for 
apoptosis in SCLC. The discovery that endogenous re-expression of the GR in SCLC 
cells is sufficient to induce apoptotic cell death by reversing a cancer-driven 
DNA methylation effect may lead to the development of novel adjunct therapies.