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Improvement of dexamethasone sensitivity by chelation of intracellular Ca2+ in pediatric acute lymphoblastic leukemia cells through the prosurvival kinase ERK1/2 deactivation

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 Ca 2+ 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.
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Souleymane Abdoul-Azize, Isabelle Dubus, Jean-Pierre Vannier. Improvement of dexamethasone sensitivity by chelation of intracellular Ca2+ in pediatric acute lymphoblastic leukemia cells through the prosurvival kinase ERK1/2 deactivation. Oncotarget, Impact journals, 2017, 8 (16), pp.27339-27352. ⟨10.18632/oncotarget.16039⟩. ⟨hal-02374408⟩

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