MEK/ERK pathway is aberrantly active in Hodgkin disease

A signaling pathway shared by CD30, CD40, and RANK that regulates cell proliferation and survival

Bei Zheng, Paolo Flumara, Yang V. Li, Georgios Georgakis, Virginia Snell, Mamoun Younes, Jean Nicolas Vauthey, Antonino Carbone, Anas Younes

Research output: Contribution to journalArticle

152 Citations (Scopus)

Abstract

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 kappaβ (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.

Original languageEnglish
Pages (from-to)1019-1027
Number of pages9
JournalBlood
Volume102
Issue number3
DOIs
Publication statusPublished - Aug 1 2003

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Mitogen-Activated Protein Kinase Kinases
Extracellular Signal-Regulated MAP Kinases
Cell proliferation
Cytoplasmic and Nuclear Receptors
Hodgkin Disease
Cell Survival
Cell Proliferation
Cells
Phosphorylation
Ligands
Mitogen-Activated Protein Kinases
CASP8 and FADD-Like Apoptosis Regulating Protein
Apoptosis
Cell Line
kappa Opioid Receptor
Myeloid Leukemia
Chemotherapy
Caspase 8
B-Cell Lymphoma
Cell death

ASJC Scopus subject areas

  • Hematology

Cite this

MEK/ERK pathway is aberrantly active in Hodgkin disease : A signaling pathway shared by CD30, CD40, and RANK that regulates cell proliferation and survival. / Zheng, Bei; Flumara, Paolo; Li, Yang V.; Georgakis, Georgios; Snell, Virginia; Younes, Mamoun; Vauthey, Jean Nicolas; Carbone, Antonino; Younes, Anas.

In: Blood, Vol. 102, No. 3, 01.08.2003, p. 1019-1027.

Research output: Contribution to journalArticle

Zheng, B, Flumara, P, Li, YV, Georgakis, G, Snell, V, Younes, M, Vauthey, JN, Carbone, A & Younes, A 2003, 'MEK/ERK pathway is aberrantly active in Hodgkin disease: A signaling pathway shared by CD30, CD40, and RANK that regulates cell proliferation and survival', Blood, vol. 102, no. 3, pp. 1019-1027. https://doi.org/10.1182/blood-2002-11-3507
Zheng, Bei ; Flumara, Paolo ; Li, Yang V. ; Georgakis, Georgios ; Snell, Virginia ; Younes, Mamoun ; Vauthey, Jean Nicolas ; Carbone, Antonino ; Younes, Anas. / MEK/ERK pathway is aberrantly active in Hodgkin disease : A signaling pathway shared by CD30, CD40, and RANK that regulates cell proliferation and survival. In: Blood. 2003 ; Vol. 102, No. 3. pp. 1019-1027.
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