Glucocorticoid receptor-mediated apoptosis: mechanisms of resistance in cancer cells

Abstract

Glucocorticoids (Gcs) are commonly used to treat patients suffering from a wide range of cancers. Their main therapeutic role is based on Gc receptor (GR)-mediated mechanisms that trigger cell death but this varies depending on the cancer type. This review aims to provide an overview of the mechanisms of Gc-induced cell death and more importantly the changes in GR that lead to resistance to Gc treatment in cancer. The three main cancer types, which are susceptible to Gc resistance and therefore loss of Gc-induced apoptotic effects, are acute lymphoblastic leukaemia, osteosarcoma and small-cell lung carcinoma. A common theme is the loss of GR function and/or a downregulation of GR expression which leads to failure of the cell death-inducing effects of Gcs. Loss of GR function is attributed to mutations in the GR gene, and in some cases a dominant-negative effect on any functional GR still present. The downregulation of GR expression can be due to decreased GR promoter activation, increased GR promoter methylation or increased expression of alternative splice isoforms of GR that have decreased transcriptional activity. Understanding the mechanisms behind Gc-triggered apoptosis and the resistance to it in these cancer types will help in further refining treatment regimens for patients and will decrease the chance of relapse caused by Gc-resistant cancer phenotypes.