Inhibition of eIF4E phosphorylation reduces cell growth and proliferation in primary central nervous system lymphoma cells.
The mRNA cap-binding protein eukaryotic initiation factor 4E (eIF4E) plays an important role in mRNA translation; its activity is implicated in cell growth and proliferation. In experimental models, eIF4E over-expression induces cellular transformation, tumorigenesis, and lymphomagenesis. The activity of eIF4E is regulated by the Akt/mTOR and MAPK/MAP kinase-interacting kinase-1 (MNK1) pathways. While investigating the participation of the MNK1/eIF4E signaling pathway in primary central nervous system lymphoma (PCNSL), we noted the over-expression of eIF4E and phosphorylated eIF4E (p-eIF4E) in specimens from PCNSL patients. Western blot analysis using B-cell lymphoma cell lines showed that eIF4E phosphorylation was serum-independent and was selectively inhibited by the MNK1 inhibitor. Furthermore, MNK1 inhibitor led to reduced cyclin D1 expression and caused inhibition of cell proliferation and cell death in human brain malignant lymphoma cell line (HKBML). Also, the growth of the subcutaneous HKBML xenografts in mice was inhibited by intraperitoneal administration of MNK1 inhibitor compared with mice treated with vehicle (P = 0.026). Our data suggest that in PCNSL cells eIF4E phosphorylation plays an important role in proliferation and our results identify inhibition of the MNK1/eIF4E pathway as a potential therapeutic target in patients with PCNSL.
Muta
Daisuke
D
Department of Neurosurgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, 860-8556, Japan.
Makino
Keishi
K
Nakamura
Hideo
H
Yano
Shigetoshi
S
Kudo
Mareina
M
Kuratsu
Jun-Ichi
J
D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D016543:Central Nervous System Neoplasms / Q000378:metabolism* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008223:Lymphoma / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
D004791:Enzyme Inhibitors; D039561:Eukaryotic Initiation Factor-4E; D047908:Intracellular Signaling Peptides and Proteins; C491395:MKNK1 protein, human; D017346:Protein Serine-Threonine Kinases