Protein kinase networks regulating glucocorticoid-induced apoptosis of hematopoietic cancer cells: fundamental aspects and practical considerations

Abstract

Glucocorticoids (GCs) are integral components in the treatment protocols of acute lymphoblastic leukemia, multiple myeloma, and non-Hodgkin lymphoma owing to their ability to induce apoptosis of these malignant cells. Resistance to GC therapy is associated with poor prognosis. Although they have been used in clinics for decades, the signal transduction pathways involved in GC-induced apoptosis have only partly been resolved. Accumulating evidence shows that this cell death process is mediated by a communication between nuclear GR affecting gene transcription of pro-apoptotic genes such as Bim, mitochondrial GR affecting the physiology of the mitochondria, and the protein kinase glycogen synthase kinase-3 (GSK3), which interacts with Bim following exposure to GCs. Prevention of Bim up-regulation, mitochondrial GR translocation, and/or GSK3 activation are common causes leading to GC therapy failure. Various protein kinases positively regulating the pro-survival Src-PI3K-Akt-mTOR and Raf-Ras-MEK-ERK signal cascades have been shown to be activated in malignant leukemic cells and antagonize GC-induced apoptosis by inhibiting GSK3 activation and Bim expression. Targeting these protein kinases has proven effective in sensitizing GR-positive malignant lymphoid cells to GC-induced apoptosis. Thus, intervening with the pro-survival kinase network in GC-resistant cells should be a good means of improving GC therapy of hematopoietic malignancies.

PPARα and fatty acid oxidation mediate glucocorticoid resistance in chronic lymphocytic leukemia

“…GCs have been shown to change the expression of apoptotic genes and alter signaling processes important for tumor growth by increasing the expression of regulatory molecules such as IkB and phosphatases. [5][6][7][8] However, despite the fact that many of the complications of GC therapy, such as diabetes and hyperlipidemia, are metabolic in nature and a major function of endogenous GCs is to turn off glucose usage and turn on fatty acid oxidation to allow cells to survive an overnight fast, 5 the possibility that the therapeutic activity of GCs in CLL is mediated through metabolism is not widely appreciated. It has been shown that GCs cause leukemia cells to undergo autophagy in some conditions, which is a response to energy deprivation.…”

“…Ligand-activated GRs transactivate genes such as IkB that inhibit signaling pathways 6 and also transrepress signaling through direct binding to kinases. 7 GCs cause CLL cells to undergo apoptosis, 8 but the processes that lead from GR phosphorylation to cell death are not fully understood. The studies in this paper were designed to provide more insight into the mechanisms of action of GCs in CLL.…”

Molecular Mechanisms Conferring Resistance/Sensitivity to Glucocorticoid-Induced Apoptosis

“…These include alterations in the activity of the glucocorticoid receptor [35,36] either due to changes in GR protein levels, presence of multiple GR variants, or post-translational modifications. GR induces apoptosis by directly modulating the expression of genes involved in cell survival/apoptosis [18,37], or affecting gene networks involved in stress signalling resulting in an apoptotic stimulus [36,38].…”

“…Resistance to glucocorticoid induced apoptosis in ALL has been attributed to several different processes and pathways including predominance of certain GR isoforms with reduced transcriptional activity [34, 145,146], either due to altered binding capacity of the receptor to other transcription factors [147,148,149,150] or co-regulators [81,151], disparate expression and consequent dissimilar balance between pro-versus anti-apoptotic members of the Bcl-2 family [18], GR mitochondrial localisation [97], autophagy [72,73,74,75], and post-translational modifications which affect GR transcription target selectivity and protein stability [22,38,89,152,153].…”

Impact of polymorphisms in apoptosis‐related genes on the outcome of childhood acute lymphoblastic leukaemia

“…Response to these agents is highly predictive of ALL outcome (Distelhorst, 2002;Kfir-Erenfeld et al, 2010). Notably, GSTM1 inhibits dexamethasone-induced apoptosis in an ALL cell line by suppression of Bim through downregulation of p38-MAPK and upregulation of NF-KB p50 (NFKB1) (Hosono et al, 2010).…”