c-JUN N-terminal kinase (JNK) is activated and contributes to tumor cell proliferation in classical Hodgkin lymphoma.
c-JUN N-terminal Kinase (JNK) is activated/phosphorylated by upstream MAPK kinases (MKK), and, in turn, phosphorylates and activates its major substrate c-JUN, a member of the activator protein-1 (AP-1) transcription factors. c-JUN is overexpressed and activated in Hodgkin and Reed Sternberg cells (HRS) of classical Hodgkin lymphoma (cHL), however, the mechanism of its activation remains unknown. JNK activation was immunohistochemically assessed in 60 cases of HL and in a control group of 151 B-cell non-Hodgkin lymphomas. The biologic effects of JNK activation in cultured HRS cells were investigated using colony formation, cell growth and viability assays and cell cycle analysis by flow cytometry. Western blotting was used to assess protein levels. p-JNK was expressed in 90% of HL, 83% of Burkitt lymphomas, 28% of mantle cell lymphomas, 23% of diffuse large B-cell lymphomas, 19% of follicular lymphomas, and 18% of extranodal marginal zone lymphomas of MALT type. None of the 48 cases of chronic lymphocytic leukemia/small lymphocytic lymphoma and 18 cases of plasma cell myeloma showed JNK phosphorylation (P < 001, Kruskall-Wallis test). Pharmacological inhibition of JNK activity in cultured HRS cells resulted in a significant decrease of cell growth, which was associated with cell cycle arrest at the G2/M phase. The cell cycle effects were linked to deactivation of c-JUN and upregulation of its known target, the cyclin-dependent kinase inhibitor p21. JNK is highly activated in HRS cells, and may contribute to uncontrolled cell cycle progression and proliferation of tumor cells in cHL.
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; First Department of Pathology, National and Kapodistrian University of Athens, Athens 11527, Greece.
Vasiliki
V
Leventaki
Department of Pathology, Medical School, University of Crete, Heraklion Crete 71003, Greece.
Elias
E
Drakos
First Department of Pathology, National and Kapodistrian University of Athens, Athens 11527, Greece.
Maria
M
Karanikou
First Department of Pathology, National and Kapodistrian University of Athens, Athens 11527, Greece.
Konstantina
K
Psatha
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Pei
P
Lin
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Ellen
E
Schlette
Laboratory of Cancer Biology, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology Hellas (FORTH), 70013 Heraklion, Greece.
Aris
A
Eliopoulos
Department of Hematology, National and Kapodistrian University of Athens, Athens 11527, Greece.
Theodoros P
TP
Vassilakopoulos
Department of Hematology, Medical School, University of Crete, Heraklion Crete 71003, Greece.
Helen
H
Papadaki
First Department of Pathology, National and Kapodistrian University of Athens, Athens 11527, Greece.
Efstratios
E
Patsouris
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
L Jeffrey
LJ
Medeiros
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; First Department of Pathology, National and Kapodistrian University of Athens, Athens 11527, Greece. Electronic address: grassidakis@hotmail.com.
George Z
GZ
Rassidakis
D002453:Cell Cycle / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006689:Hodgkin Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D016539:Reed-Sternberg Cells / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction
D048031:JNK Mitogen-Activated Protein Kinases
Cell cycle; Hodgkin lymphoma; JNK; Non-Hodgkin lymphoma; c-JUN; p21