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.

Identification and molecular characterization of cellular factors required for glucocorticoid receptor-mediated mRNA decay

“…The induced DNA damage could activate ATM kinase and phosphorylate UPF1 in the presence of GC, consequently enhancing GMD efficiency. Therefore, it is most likely that the preference of GMD for ATM may couple DNA damage responses to GMD target mRNA stability, contributing to the regulation of many physiologic events such as apoptosis (Schlossmacher et al 2011).…”

Integrative genomic analyses of the histamine H1 receptor and its role in cancer prediction

“…used for the treatment of lymphoid malignancy due to their marked effects on cell cycle progression and apoptosis (34). Glucocorticoids are able to alter signaling in key survival pathways and this can result in reversible growth arrest or cell death in certain cell types (34)(35)(36).…”

“…Glucocorticoids are able to alter signaling in key survival pathways and this can result in reversible growth arrest or cell death in certain cell types (34)(35)(36). STAT5A is a member of the STAT family of transcription factors.…”

Optimization of immunosuppressive medication upon liver transplantation against HCC recurrence

“…Steroids modulate cellular and inflammatory responses by altering transcription of target genes in a cell type specific manner (37). The majority of IS protocols in the initial months after liver transplantation involve the use of steroids.…”