Converting cell lines representing hematological malignancies from glucocorticoid-resistant to glucocorticoid-sensitive: Signaling pathway interactions☆

Abstract 

Mitogen-activated protein kinases (MAPKs), protein kinase A (PKA) and mTOR pathways modulate the apoptotic effects of glucocorticoids (GCs) in human lymphoblastic leukemia CEM cells. We now show that manipulation of these pathways converts several cell lines, representing other lymphoid malignancies, from GC-resistant to GC-sensitive. Basal levels of phosphorylated JNK and ERK were elevated in the GC-resistant cells. Treatments that directly or indirectly reduced phosphorylated JNK and ERK resulted in Dex sensitivity in five resistant lymphoid cell lines. Sensitivity to GC-driven apoptosis correlated with GC-dependent increases in phosphorylated and total glucocorticoid receptor, and in increased levels of the pro-apoptotic protein Bim.

Abbreviations: ALL, acute lymphoblastic leukemia, AML, acute myelogenous leukemia, CML, chronic myelogenous leukemia, Dex, dexamethasone, FBS, fetal bovine serum, Fsk, forskolin, GR, glucocorticoid receptor, IDV, individual densitometric values, ip, cell permeable, JNK, inhibitory peptide, MAPK, mitogen-activated protein kinase, PKA, protein kinase A, PI, propidium iodide, S211, serine 211, ATCC, American Type Culture Collection, ERK, extracellular-signal regulated kinase, JNK, Jun N-terminal kinase, MEK, mitogen-activated protein kinase kinase

Keywords: Glucocorticoid receptor, Myeloma, Leukemia, MAPK, mTOR, PKA