Glucocorticoid-Induced Apoptosis: Revisited: A Novel Role for Glucocorticoid Receptor Translocation to the Mitochondria

Abstract

Recent data cast new light on the mechanisms by which glucocorticoids (GCs) elicit apoptosis of thymocytes and leukemia cells. Here we attempt to integrate recent studies by others and us, which provide a novel insight to this apoptotic process. In the last few years it was made clear that there is a tight cooperation between genomic and non-genomic effects exerted by GC receptors (GRs). GC invokes major alterations in the gene expression profile through GR-mediated transactivation and transrepression, which ultimately tip the balance between pro-survival and pro-apoptotic proteins. Although essential in shaping the cell's proteome, these genomic effects are insufficient to elicit apoptotic death and additional signals are required for activating the pro-apoptotic proteins. Several non-genomic effects have been described that occur immediately following exposure to GC, which are imperative for the induction of apoptosis. We have recently observed that GC induces instant GR translocation to the mitochondria in GC-sensitive, but not in GC-resistant, T lymphoid cells. This response contrasts the nuclear translocation of GR occurring in both cell types. We propose that the sustained elevation of GR in the mitochondria following GC exposure is crucial for triggering apoptosis.

Steroid and thyroid hormone receptors in mitochondria

“…Several genes of the extrinsic and intrinsic death pathways are expressed in a proapoptotic manner in sensitive lymphoid cells treated with glucocorticoids, although additional signals are necessary to activate the apoptotic process. In this respect, Sionov et al (50,117) using T-lymphoid cell lines varying in sensitivity toward glucocorticoids have revealed a direct effect of the mitochondrial glucocorticoid receptor in the apoptotic process. In these cells, glucocorticoids induce a translocation of the cognate receptor from the cytoplasm to mitochondria, whereas in glucocorticoid resistant cells no such movement of GR is evident.…”

Molecular Mechanisms Conferring Resistance/Sensitivity to Glucocorticoid-Induced Apoptosis

“…The glucocorticoid receptor translocates to mitochondria [97,100,101,102], in various cells including rat brain and various other tissues' mitochondria [99], as well as lymphoma cells [97]. GR translocation to the nucleus occurs in both glucocorticoid-sensitive and glucocorticoid-resistant cells, whereas in contrast, GR translocation into mitochondria occurs only in the glucocorticoid-sensitive and not the resistant cells [97,103]. The mechanisms by which GR translocates to mitochondria and its effects on the regulation of the expression of mitochondrially encoded genes have been partially elucidated [97,100,101,102] and require further investigation.…”

Staurosporine Sensitizes T Lymphoma Cells to Glucocorticoid-Induced Apoptosis: Role of Nur77 and Bcl-2

“…1 In contrary, acute and chronic myelogenic leukemias (AML and PML) are usually resistant to this treatment. The reason for this differential response to GC is still unclear.…”

“…The variable sensitivities of lymphoma and leukemia cells to GC-induced apoptosis may, in part, be explained by differential intracellular trafficking of the glucocorticoid receptor (GR) in response to GC, and variable expressions of GR or anti-apoptotic proteins. 1,2 Additional factors may also influence the cell fate after exposure to GC, such as the expression of SRG3, 3 Notch1 4 and b-catenin. 5 Hence, combinatory treatment protocols are needed that would increase the therapeutic efficacy of GC and retain the apoptotic sensitivity of the target cells over time.…”

“…1,12 Some distinct signal transduction pathways leading to GC-induced apoptosis have been described depending on the cell type. 13,14 In thymocytes, the GC apoptotic pathway involves Src and phosphatidylinositol-specific phospholipase-C activation, but not p38.…”