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Mechanisms of glucocorticoid-induced apoptosis in small cell lung cancer

Platt, Eleanor

[Thesis]. Manchester, UK: The University of Manchester; 2014.

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Abstract

Small cell lung cancer (SCLC) tumours are very aggressive. Patients often present with metastases at diagnosis and prognosis is very poor. SCLC cell lines have been shown to be resistant to glucocorticoids due to impaired glucocorticoid receptor (GR) expression (Gaitan et al, 1995; Ray et al, 1996). Restoration of GR expression in these cells triggers apoptosis in vitro (Sommer et al, 2007) and in vivo (Sommer et al, 2010). It is possible that loss of GR expression plays a role in SCLC pathogenesis and therefore GR could be considered as a novel tumour suppressor gene for SCLC.Over-expression of exogenous GR restores glucocorticoid sensitivity in SCLC cells and triggers glucocorticoid-induced apoptosis, both in vitro (Sommer et al, 2007) and in vivo. (Sommer et al, 2010). The mechanisms underlying regulation of GR expression and glucocorticoid-induced apoptosis in these cells are not fully understood. This thesis aims to investigate the regulation of GR in relation to glucocorticoid-induced apoptosis in SCLC cell lines.Quantitative PCR data showed that GR gene expression was not altered by glucocorticoid treatment in SCLC cell line DMS-79 cells. Levels of GR protein were seen to be very low in these cells and were not affected by an increase in cell number / density or treatment with low concentrations of glucocorticoids. A decrease in GR protein levels was observed following treatment of DMS-79 cells with very high concentrations of dexamethasone or hydrocortisone, however GR protein levels returned to that of untreated cells following removal of glucocorticoids. GR protein levels were also found to be very low in vivo, as demonstrated by immunohistochemistry of DMS-79 cell xenografts. This suggests that DMS-79 cells tightly regulate GR protein levels in order to evade glucocorticoid-induced apoptosis.A number of approaches to increase GR protein levels in DMS-79 cells were investigated, with a view to conferring glucocorticoid sensitivity to these cells. DMS-79 cells did not show auto-upregulation of GR from promoter 1A following treatment with glucocorticoids and attempts to stably transfect these cells with a construct containing GR under the control of a tetracycline-inducible promoter were unsuccessful. Further investigation into approaches to increase GR protein levels should be undertaken since understanding the mechanisms underlying glucocorticoid-induced apoptosis may provide insight into novel therapeutic approaches for SCLC patients.

Layman's Abstract

Small cell lung cancer (SCLC) is a very aggressive form of lung cancer. Tumours can quickly spread throughout the patient’s body and treatment of SCLC is very difficult. We use human SCLC cells, derived from patient tumours as a way to investigate how to kill these tumour cells. The glucocorticoid receptor (GR) is a regulator which can help kill tumour cells. We have found that SCLC cells have less GR than non-SCLC cells, allowing these cells to survive and grow. Increasing the amount of GR in SCLC cell lines makes these cells more likely to die. Therefore it is important to understand ways to increase GR and force these cancer cells to die since this may provide a treatment for patients with SCLC.