Abstract
The initial response of lymphoid malignancies to glucocorticoids (GCs) is a critical parameter predicting successful treatment. Although being known as a strong inducer of apoptosis in lymphoid cells for almost a century, the signaling pathways regulating the susceptibility of the cells to GCs are only partly revealed. There is still a need to develop clinical tests that can predict the outcome of GC therapy. In this paper, I discuss important parameters modulating the pro-apoptotic effects of GCs, with a specific emphasis on the microRNA world comprised of small players with big impacts. The journey through the multifaceted complexity of GC-induced apoptosis brings forth explanations for the differential treatment response and raises potential strategies for overcoming drug resistance.
Highlights
Glucocorticoids (GCs) are among the most effective drugs used in the treatment of hematopoietic malignancies of the lymphoid lineage in virtue of their ability to induce apoptosis of these cancerous cells [1,2,3]. e main hematopoietic cancer types that respond well to germinal center (GC) therapy include T acute lymphoblastic leukemia (T-ALL), chronic B lymphocytic leukemia (CLL), multiple myeloma (MM), Hodgkin’s lymphoma (HL), and non-Hodgkin’s lymphoma (NHL)
Main factors affecting the response to GC include the basal and inducible glucocorticoid receptor (GR) expression levels, the induction of and basal expression of genes involved in the intrinsic apoptotic pathway, the ability of GR to translocate to the mitochondria, the activity of GSK3, the general protein kinase activation pro le of the cell prior to and following GC therapy, the expression pro le of anti-apoptotic proteins, and the activities of prosurvival signaling pathways. e main traits will only be brie y described here as these have been extensively reviewed elsewhere [30, 31, 99, 150,151,152,153], and the scope of this paper is to provide updated data with a speci c focus on the microRNA world that has emerged to comprise important regulators of most biological processes
Interruption of any of the proapoptotic processes may lead to drug resistance
Summary
Most primary ALL cells showed upregulation of GR expression upon prednisolone treatment regardless of their phenotype or sensitivity to GC-induced apoptosis, suggesting that other factors are more dominant for conferring a GC-resistant phenotype in these cells [29, 170, 182,183,184]. Essential downstream mediators are Bak and Bax [222] that are activated by Bim. the thioredoxininteracting protein Txnip (VDUP1/TBP-2) has been shown to be upregulated by GC and could contribute to GC-induced apoptosis in one mouse lymphoma cell line [223]. E activity of FoxO transcription factors is tightly regulated, inhibited by Akt and ERK signaling, while promoted by p38 signaling [232,233,234,235,236] Both ERK1/2 and Akt antagonize apoptosis by reducing the Bim expression level. PTEN expression can be repressed by a range of microRNAs including the miR-17∼92 cluster [247, 248], miR-106b∼25 [314], miR-21 [269], miR-26a [253, 315], miR-29b [316], miR-214 [317, 318], miR-216a and miR-217 [319], miR-212 [320], miR-221, and miR-222 [321] (Figure 3)
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