MEK/ERK pathway is aberrantly active in Hodgkin disease: a signaling pathway shared by CD30, CD40, and RANK that regulates cell proliferation and survival.
The mitogen-activated protein kinase (MAPK) (also called extracellular signal-regulated kinase [ERK]) pathway has been implicated in malignant transformation and in the regulation of cellular growth and proliferation of several tumor types, but its expression and function in Hodgkin disease (HD) are unknown. We report here that the active phosphorylated form of MAPK/ERK is aberrantly expressed in cultured and primary HD cells. Inhibition of the upstream MAPK kinase (also called MEK) by the small molecule UO126 inhibited the phosphorylation of ERK and demonstrated a dose- and time-dependent antiproliferative activity in HD cell lines. UO126 modulated the levels of several intracellular proteins including B-cell lymphoma protein 2 (Bcl-2), myeloid cell leukemia-1 (Mcl-1) and caspase 8 homolog FLICE-inhibitory protein (cFLIP), and induced G2M cell-cycle arrest or apoptosis. Furthermore, UO126 potentiated the activity of apoliprotein 2/tumor necrosis factor-related apoptosis-inducing ligand (APO2L/TRAIL) and chemotherapy-induced cell death. Activation of CD30, CD40, and receptor activator of nuclear kappabeta (RANK) receptors in HD cells by their respective ligands increased ERK phosphorylation above the basal level and promoted HD cell survival. UO126 inhibited basal and ligand-induced ERK phosphorylation, and inhibited ligand-induced cell survival of HD cell lines. These findings provide a proof-of-principle that inhibition of the MEK/ERK pathway may have therapeutic value in HD.
Zheng
Bei
B
Department of Lymphoma/Myeloma, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 429, Houston, TX 77030, USA.
Fiumara
Paolo
P
Li
Yang V
YV
Georgakis
Georgios
G
Snell
Virginia
V
Younes
Mamoun
M
Vauthey
Jean Nicolas
JN
Carbone
Antonino
A
Younes
Anas
A
D000970:Antineoplastic Agents / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins; D002070:Butadienes / Q000494:pharmacology; D019013:CD40 Antigens; D002455:Cell Division; D002470:Cell Survival; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006023:Glycoproteins; D006689:Hodgkin Disease / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D017730:Ki-1 Antigen; D008198:Lymph Nodes / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism* / Q000502:physiology; D009570:Nitriles / Q000494:pharmacology; D053244:Osteoprotegerin; D010766:Phosphorylation; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D002070:Butadienes; D019013:CD40 Antigens; D004791:Enzyme Inhibitors; D006023:Glycoproteins; D017730:Ki-1 Antigen; D008562:Membrane Glycoproteins; D009570:Nitriles; D053244:Osteoprotegerin; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C506030:TNFRSF11B protein, human; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; C113580:U 0126; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases