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National Institute of Environmental Health Sciences

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Publication Detail

Title: Neurotrophin signaling through tropomyosin receptor kinases contributes to survival and proliferation of non-Hodgkin lymphoma.

Authors: Sniderhan, Lynn F; Garcia-Bates, Tatiana M; Burgart, Michael; Bernstein, Steven H; Phipps, Richard P; Maggirwar, Sanjay B

Published In Exp Hematol, (2009 Nov)

Abstract: 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.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.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.Thus, Trk receptors represent a novel therapeutic target for the treatment of NHL.

PubMed ID: 19716854 Exiting the NIEHS site

MeSH Terms: Apoptosis/drug effects; Autocrine Communication/drug effects; Autocrine Communication/physiology; B-Lymphocytes/drug effects; B-Lymphocytes/enzymology; Brain-Derived Neurotrophic Factor/analysis; Carbazoles/pharmacology; Cell Division/drug effects; Cell Division/physiology; Cell Line, Tumor/drug effects; Cell Line, Tumor/enzymology; Culture Media, Conditioned/chemistry; DNA Replication/drug effects; Humans; Indole Alkaloids/pharmacology; Lymphoma, Large B-Cell, Diffuse/enzymology; Lymphoma, Large B-Cell, Diffuse/genetics; Lymphoma, Large B-Cell, Diffuse/pathology; Lymphoma, Non-Hodgkin/drug therapy; Lymphoma, Non-Hodgkin/enzymology*; Lymphoma, Non-Hodgkin/genetics; Lymphoma, Non-Hodgkin/pathology; NF-kappa B/antagonists & inhibitors; Neoplasm Proteins/analysis; Neoplasm Proteins/biosynthesis; Neoplasm Proteins/genetics; Neoplasm Proteins/physiology*; Nerve Growth Factor/analysis; Nerve Growth Factors/physiology*; RNA, Messenger/biosynthesis; RNA, Neoplasm/biosynthesis; Receptors, Nerve Growth Factor/antagonists & inhibitors; Receptors, Nerve Growth Factor/biosynthesis; Receptors, Nerve Growth Factor/drug effects; Receptors, Nerve Growth Factor/genetics; Receptors, Nerve Growth Factor/physiology*; Signal Transduction/drug effects; Tyrphostins/pharmacology

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