Glucocorticoid receptor-mediated apoptosis in small-cell lung cancer requires interaction with BCL2

Abstract

Small-cell lung cancer (SCLC) tumours are highly aggressive. At the time of diagnosis, patients have often developed metastases, and overall prognosis is particularly poor, making effective treatment difficult. Novel mechanisms need to be identified as treatment targets. We have previously found low levels of the glucocorticoid receptor (GR) in SCLC cell lines and demonstrated that over-expression of GR increases tumour cell death both in vitro and in vivo. We hypothesise that low levels of GR impair its inhibitory effect on BCL2 and thus provide a survival advantage to SCLC cell lines. The mechanism behind GR-induced apoptosis is currently unknown; therefore, pro- and anti-apoptotic genes were investigated for their role in GR-mediated apoptosis signalling. We found that over-expression of wtGR via retroviral transduction causes the DMS 79 SCLC cell line to undergo caspase-mediated apoptosis within 72 h. Neither BAD nor BCL2L11 (BIM) mRNA and protein levels were affected by GR restoration implying that GR does not trigger apoptosis in the SCLC cell lines by up-regulating these pro-apoptotic genes. The anti-apoptotic BCL2 gene was significantly overexpressed in six SCLC cell lines and the BCL2 inhibitor ABT-737 increased apoptosis in all three cell lines tested. GR interacted with BCL2 in DMS 153, DMS 79 and COR-L42 cell lines, suggesting that a protein interaction between GR and BCL2 could play a role in GR-induced apoptosis. A deeper understanding of the molecular mechanism for increasing GR expression in SCLC could provide novel treatment strategies in the future.