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 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-MAPK and JNK could be blocked by respective inhibitors (SB203580 for p38-MAPK 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-MAPK and JNK, and might be an attractive new agent for treatment of GC-resistant ALL.