title: Neurotrophin signaling through tropomyosin receptor kinases contributes to survival and proliferation of non-Hodgkin lymphoma.
abstract: OBJECTIVE
  Neurotrophin receptor signaling has been increasingly recognized as an important factor in the development and progression of a variety of malignancies. In order to analyze the potential contribution of neurotrophin signaling to lymphoma cell survival, we investigated the role of a neurotrophin axis in promoting survival and proliferation of non-Hodgkin lymphoma (NHL) cells.
  
  
  METHODS
  The role of neurotrophins in the survival and proliferation of NHL cells was determined by exposing cells to the Trk-specific inhibitor, K252a, and then performing (3)H-thymidine incorporation and Annexin-V/propidium iodide staining. The involvement of nuclear factor-kappaB (NF-kappaB) in this process was studied using Western blot, electrophoretic mobility shift assay, and immunofluorescence assays.
  
  
  RESULTS
  Here we demonstrate that both primary NHL cells and diffuse large B-cell lymphoma cell lines express Trk receptors and their neurotrophin ligands. Furthermore, these cells are sensitive to the Trk-specific inhibitor, K252a, as evidenced by the inhibition of proliferation and/or induction of apoptosis. Analysis of the mechanism into the effects of K252a revealed that, in the OCI-LY3 cell line, K252a induced a subnuclear distribution of NF-kappaB resulting in the sequestration of RelA in the nucleolus, thereby inhibiting NF-kappaB-dependent gene transcription. This results in the loss of interleukin-6 production; a known survival-promoting signal for OCI-LY3, as well as many primary diffuse large B-cell lymphomas.
  
  
  CONCLUSIONS
  Thus, Trk receptors represent a novel therapeutic target for the treatment of NHL.
authors.affiliation: Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
authors.forename: Lynn F
authors.initials: LF
authors.lastname: Sniderhan
authors.forename: Tatiana M
authors.initials: TM
authors.lastname: Garcia-Bates
authors.forename: Michael
authors.initials: M
authors.lastname: Burgart
authors.forename: Steven H
authors.initials: SH
authors.lastname: Bernstein
authors.forename: Richard P
authors.initials: RP
authors.lastname: Phipps
authors.forename: Sanjay B
authors.initials: SB
authors.lastname: Maggirwar
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D019898:Autocrine Communication / Q000187:drug effects / Q000502:physiology; D001402:B-Lymphocytes / Q000187:drug effects / Q000201:enzymology; D019208:Brain-Derived Neurotrophic Factor / Q000032:analysis; D002227:Carbazoles / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor / Q000187:drug effects / Q000201:enzymology; D017077:Culture Media, Conditioned / Q000737:chemistry; D004261:DNA Replication / Q000187:drug effects; D006801:Humans; D026121:Indole Alkaloids / Q000494:pharmacology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009363:Neoplasm Proteins / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D020932:Nerve Growth Factor / Q000032:analysis; D009414:Nerve Growth Factors / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D017475:Receptors, Nerve Growth Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: C081020:AG-879; D019208:Brain-Derived Neurotrophic Factor; D002227:Carbazoles; D017077:Culture Media, Conditioned; D026121:Indole Alkaloids; D016328:NF-kappa B; D009363:Neoplasm Proteins; D009414:Nerve Growth Factors; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D017475:Receptors, Nerve Growth Factor; D020032:Tyrphostins; D020932:Nerve Growth Factor; C049985:staurosporine aglycone