Pro-apoptotic protein BIM in apoptosis of glucocorticoid-sensitive and -resistant acute lymphoblastic leukemia CEM cells

Abstract

Although glucocorticoids (GCs) have been used to treat acute lymphoblast leukemia (ALL) for decades, the mechanisms of GC sensitivity and resistance in ALL cells are poorly understood. This study investigated the role and mechanisms of pro-apoptotic protein BIM in apoptosis of GC-sensitive and- resistant ALL cells. The dramatic apoptosis was observed in GC-sensitive CEM-C7 cells after incubated with DEX for 48 h, while not in GC-resistant CEM-C1 cells. The significant up-regulation of BIM in CEM-C7 cells induced by DEX was also observed, but no up-regulation of BIM was detected in DEX-induced CEM-C1 cells. When treated with DEX plus RU486, a glucocorticoid receptor blocker, the apoptosis and BIM expression of CEM-C7 cells were canceled. P38MAPK-blocking pharmacon SB203580 also significantly inhibited the up-regulation of BIM in CEM-C7 cells. These suggested that the absence of BIM up-regulation is one of the important mechanisms of GC resistance, GC-GR conjugation is indispensible in both GC-induced apoptosis and up-regulation of BIM, and p38 MAPK signal pathway is also involved in this process.

Loss of TBL1XR1 Disrupts Glucocorticoid Receptor Recruitment to Chromatin and Results in Glucocorticoid Resistance in a B-Lymphoblastic Leukemia Model

“…Decreased induction of prednisolone-responsive genes upon TBL1XR1 knockdown was also observed upon a shorter 3-h prednisolone exposure (data not shown). Decreased expression of pro-apoptotic protein BIM has been associated with glucocorticoid resistance in ALL (35,36). BIM induction by prednisolone was not effected by TBL1XR1 knockdown (Fig.…”

“…The induction of BIM upon prednisolone exposure is not reduced by TBL1XR1 knockdown. Because BIM induction is important for prednisolone-induced apoptosis (35,36), BIM induction may account for remaining levels of prednisolone-induced apoptosis observed in the TBL1XR1 knockdown lines. TBL1XR1 is responsible for maintaining appropriate levels of the corepressor NCoR1 (11,31), and decreased levels of TBL1XR1 result in a reciprocal increased level of NCoR1.…”

Expression differences in TEL-AML1 fusion gene in leukemia glucocorticoid-sensitive and -resistant cell lines

“…By activating the glucocorticoid response element in the nucleus, apoptosis genes are activated by transcription or regulatory factors (nuclear factor-kB or activator protein-1) and transcription is activated. Expression of growth genes is thereby inhibited, resulting in cell apoptosis (Zhao et al, 2011). Studies confirmed that an anomaly at any link in this pathway can lead to GC-resistance (Bachmann et al, 2010).…”

Glucocorticoid Receptor Knockdown Decreases the Antioxidant Protection of B16 Melanoma Cells: An Endocrine System-Related Mechanism that Compromises Metastatic Cell Resistance to Vascular Endothelium-Induced Tumor Cytotoxicity

“…Recent studies of the pro-apoptotic protein BIM, which is involved in the apoptosis of glucocorticoid-sensitive (CEM-C7) and -resistant (CEM-C1) acute lymphoblastic leukemia CEM cells, have shown that treatment with dexamethasone plus RU486 blocked apoptosis and BIM expression in CEM-C7 cells [65]. P38MAPK-blocking pharmacon SB203580 also significantly inhibits the up-regulation of BIM in CEM-C7 cells [65].…”

“…Recent studies of the pro-apoptotic protein BIM, which is involved in the apoptosis of glucocorticoid-sensitive (CEM-C7) and -resistant (CEM-C1) acute lymphoblastic leukemia CEM cells, have shown that treatment with dexamethasone plus RU486 blocked apoptosis and BIM expression in CEM-C7 cells [65]. P38MAPK-blocking pharmacon SB203580 also significantly inhibits the up-regulation of BIM in CEM-C7 cells [65]. This evidence suggests that the absence of BIM up-regulation is one of the important mechanisms underlying glucocorticoid resistance, and glucocorticoid-GCR conjugation is indispensable in both glucocorticoid-induced apoptosis and BIM up-regulation.…”