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Prepublished online as a Blood First Edition Paper on April 10, 2003; DOI 10.1182/blood-2002-11-3507.
Submitted November 19, 2002
Accepted March 24, 2003
MEK/ERK pathway is constitutively active in Hodgkin disease: a shared signaling pathway among CD30, CD40, and RANK that regulates cell proliferation and survival
Bei Zheng, Paolo Fiumara, Yang Li, Georgios V Georgakis, Virginia Snell, Mamoun Younes, Jean N Vauthey, Antonino Carbone, and Anas Younes*
Department of Lymphoma/Myeloma, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
Department of Pathology, Baylor College of Medicine, Houston, TX, USA
Department of Pathology, National Institute of Cancer, Aviano, Italy
* Corresponding author; email: ayounes{at}mdanderson.org.
The mitogen-activated protein kinase (MAPK, also called 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) is unknown. We report here that the active phosphorylated form of MAPK/ERK is constitutively 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 Bcl-2, Mcl-1, and cFLIP, and induced G2M cell cycle arrest or apoptosis. Furthermore, UO126 potentiated the activity of APO2L/TRAIL and chemotherapy-induced cell death. Activation of CD30, CD40, and RANK receptors in HD cells by their prospective ligands increased ERK phosphorylation above the basal level. UO126 not only inhibited the basal phosphorylation level of ERK, but also inhibited ligand-induced ERK phosphorylation in HD cell lines. These findings demonstrate that ERK is constitutively active in HD cells and provides a proof-of-principle that inhibition of the MEK/ERK pathway may have therapeutic value in HD.
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