Anisomycin Induces Apoptosis of Glucocorticoid Resistant Acute Lymphoblastic Leukemia CEM-C1 Cells via Activation of Mitogen-Activated Protein Kinases p38 and JNK

Abstract

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.

Phosphorylation of serine 4642 in the COOH-extremity of plectin by MNK2 and PKA modulates its interaction with intermediate filaments

“…6A). Upon increasing incubation times with anisomycin and sorbitol there was a progressive degradation of plectin, most likely reflecting proteolysis during apoptosis (Stegh et al, 2000) induced by these compounds (Marfe et al, 2009;Liu et al, 2013). In agreement with previous reports (Raingeaud et al, 1995;Kayali et al, 2000;Bagowski et al, 2003), we observed a rapid and long lasting stimulation of ERK1/2 in HeLa cells incubated with EGF, PMA and sorbitol, whereas anisomycin was a poor stimulator of ERK1/2.…”

Quantitative proteomic analysis reveals maturation as a mechanism underlying glucocorticoid resistance in B lineage ALL and re‐sensitization by JNK inhibition

“…Thus, JNK inhibition, or a key downstream JNK target, may allow GC sensitization in both B‐ and T‐lineage ALL . Our data adds to the increasing evidence that MAPK pathways modulate GC response in ALL cells and, more recently, anisomycin, a protein synthesis inhibitor and p38 (also termed MAPK14) agonist, was shown to resensitize GC response via activation of both p38 and JNK (Miller et al , ; Garza et al , ; Liu et al , ).…”

HMG-CoA reductase inhibitors induce apoptosis of lymphoma cells by promoting ROS generation and regulating Akt, Erk and p38 signals via suppression of mevalonate pathway

“…36 Furthermore, p38 pathway-mediated apoptosis was also observed in different cell types. 37, 38 In addition, Erk activation is essential for carcinogenesis, 39 and constitutively activated Erk is found in a variety of human cancers. 40 …”