Glucocorticoid (GC) resistance in children with acute lymphoblastic leukemia (ALL) usually resulted in the failure of treatment. Exploring new agents to overcome GC resistance is important. Here we reported for the first time that low-dose anisomycin has the potential to sensitize GC-resistant T-ALL CEM-C1 cells to dexamethasone (DEX). Compared with the use of DEX or low-dose anisomycin alone, co-treatment with them resulted in a significant increase of growth inhibition, apoptosis and cell cycle arrest in CEM-C1 cells through induction of activated caspase-3 and up-regulation of Bim, p21and p27, and down-regulation of Mcl-1, Bcl-2, c-myc, cyclin A and cyclin D1. Furthermore, co-treatment remarkably activated glucocorticoid receptor (GR), p38-MAPK and JNK, and all of them were canceled only by the GR inhibitor RU486, indicating GR might be an at the upstream of GR-p38-MAPK/JNK pathway. We conclude that low-dose anisomycin sensitizes GC-resistant CEM-C1 cells to DEX and this effect is mediated, at least in part, by activation of the GR-p38-MAPK/JNK signaling pathway.

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.

Glucocorticoids (GCs) resistance is frequently encountered in children with acute lymphoblastic leukemia (ALL), especially in T-ALL, which usually results in failure of treatment. To find new agent to overcome GC resistance of ALL is an urgent problem. Here we investigated potential effect of anisomycin on GC-resistant T-ALL CEM-C1 cells and explored involved molecular mechanisms. Dramatic growth inhibition and apoptosis in GC resistant CEM-C1 cells and GC-sensitive CEM-C7 cells induced by anisomycin were observed, which presented in a concentration- and time-dependent manner. Correspondingly, anisomycin induced cleaved caspase-3 and up-regulation of pro-apoptotic proteins (BimEL and Bad), meanwhile down-regulation of anti-apoptotic proteins (Mcl-1 and Bcl-2), both in a dose- and time-dependent manner in GC resistant CEM-C1 cells. Anisomycin also induced cell cycle arrest at G0/G1 phase in CEM-C1 cells through increasing expressions of p21 and p27, and attenuating the expression of cyclinA. The rapid up-regulation of phosphorylated mitogen-activated protein kinases (MAPKs) p38 and Jun N-terminal kinase (JNK) were observed after CEM-C1 cells were incubated with anisomycin. The activation of p38 and JNK could be blocked by respective inhibitors (SB203580 for p38 and SP600125 for JNK) accompanied with the inhibition of apoptosis and changes of apoptosis associated proteins in CEM-C1 cells. These results suggested that anisomycin induced apoptosis of CEM-C1 cells via activation of p38 and JNK, and might be an attractive new agent for treatment of GC-resistant ALL.

Congenital heart disease (CHD) is a common cardiac disorder in humans. Despite many advances in the understanding of CHD and the identification of many associated genes, the fundamental etiology for the majority of cases remains unclear. The planar cell polarity (PCP) signaling pathway, responsible for tissue polarity in Drosophila and gastrulation movements and cardiogenesis in vertebrates, has been shown to play multiple roles during cardiac differentiation and development. The disrupted function of PCP signaling is connected to some CHDs. Here, we summarize our current understanding of how PCP factors affect the pathogenesis of CHD.

The mutation,p.Y657S,in SH2 domain of STAT3 is a disease-causing mutation in the boy with HIES.