Abstract
Previous studies have demonstrated that glucocorticoid hormones, including dexamethasone, induced alterations in intracellular calcium homeostasis in acute lymphoblastic leukemia (ALL) cells. However, the mechanism by which intracellular calcium homeostasis participates in dexamethasone sensitivity and resistance on ALL cells remains elusive. Here, we found that treatment of cells with dexamethasone resulted in increased intracellular calcium concentrations through store-operated calcium entry stimulation, which was curtailed by store-operated calcium channel blockers. We show that BAPTA-AM, an intracellular Ca2+ chelator, synergistically enhances dexamethasone lethality in two human ALL cell lines and in three primary specimens. This effect correlated with the inhibition of the prosurvival kinase ERK1/2 signaling pathway. Chelating intracellular calcium with Bapta-AM or inhibiting ERK1/2 with PD98059 significantly potentiated dexamethasone-induced mitochondrial membrane potential collapse, reactive oxygen species production, cytochrome c release, caspase-3 activity, and cell death. Moreover, we show that thapsigargin elevates intracellular free calcium ion level, and activates ERK1/2 signaling, resulting in the inhibition of dexamethasone-induced ALL cells apoptosis. Together, these results indicate that calcium-related ERK1/2 signaling pathway contributes to protect cells from dexamethasone sensitivity by limiting mitochondrial apoptotic pathway. This report provides a novel resistance pathway underlying the regulatory effect of dexamethasone on ALL cells.
Highlights
Glucocorticoids are the most common compounds used in the treatment of lymphoid malignancies, including acute lymphoblastic leukemia (ALL), because of their abilities to induce cell death [1]
The dose-response graph of Bapta-AM indicated that concentrations as low as 5 μM Bapta-AM significantly increased the lethality of 100 nM dexamethasone in ALL cell lines (Figure 1D)
The apoptosis rate was slightly increased with Bapta-AM or dexamethasone alone treatment, but significantly increased by co-treatment in both ALL cell lines when compared to control or dexamethasone alone (Figure 1G, 1H), confirming the results obtained by the MTT assay
Summary
Glucocorticoids are the most common compounds used in the treatment of lymphoid malignancies, including acute lymphoblastic leukemia (ALL), because of their abilities to induce cell death [1]. Calcium ions are key regulators of several cellular mechanisms, including cell growth and death [6]. It has been reported that glucocorticoids (dexamethasone or corticosterone) induced a decrease in [Ca2+]i in neurons and astrocytes [7], and in T lymphocytes [8]. These observations were opposite to many reports indicating that glucocorticoid increases Ca2+ signaling in murine [9]
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