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. MATERIALS AND 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. CONCLUSION: Thus, Trk receptors represent a novel therapeutic target for the treatment of NHL.
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. MATERIALS AND 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. CONCLUSION: Thus, Trk receptors represent a novel therapeutic target for the treatment of NHL.
Authors: Lloyd T Lam; R Eric Davis; Jackie Pierce; Michael Hepperle; Yajun Xu; Maria Hottelet; Yuhua Nong; Danyi Wen; Julian Adams; Lenny Dang; Louis M Staudt Journal: Clin Cancer Res Date: 2005-01-01 Impact factor: 12.531
Authors: R C Bargou; F Emmerich; D Krappmann; K Bommert; M Y Mapara; W Arnold; H D Royer; E Grinstein; A Greiner; C Scheidereit; B Dörken Journal: J Clin Invest Date: 1997-12-15 Impact factor: 14.808
Authors: C A Dionne; A M Camoratto; J P Jani; E Emerson; N Neff; J L Vaught; C Murakata; D Djakiew; J Lamb; S Bova; D George; J T Isaacs Journal: Clin Cancer Res Date: 1998-08 Impact factor: 12.531
Authors: Sandeep S Dave; George Wright; Bruce Tan; Andreas Rosenwald; Randy D Gascoyne; Wing C Chan; Richard I Fisher; Rita M Braziel; Lisa M Rimsza; Thomas M Grogan; Thomas P Miller; Michael LeBlanc; Timothy C Greiner; Dennis D Weisenburger; James C Lynch; Julie Vose; James O Armitage; Erlend B Smeland; Stein Kvaloy; Harald Holte; Jan Delabie; Joseph M Connors; Peter M Lansdorp; Qin Ouyang; T Andrew Lister; Andrew J Davies; Andrew J Norton; H Konrad Muller-Hermelink; German Ott; Elias Campo; Emilio Montserrat; Wyndham H Wilson; Elaine S Jaffe; Richard Simon; Liming Yang; John Powell; Hong Zhao; Neta Goldschmidt; Michael Chiorazzi; Louis M Staudt Journal: N Engl J Med Date: 2004-11-18 Impact factor: 91.245
Authors: M Kerschensteiner; E Gallmeier; L Behrens; V V Leal; T Misgeld; W E Klinkert; R Kolbeck; E Hoppe; R L Oropeza-Wekerle; I Bartke; C Stadelmann; H Lassmann; H Wekerle; R Hohlfeld Journal: J Exp Med Date: 1999-03-01 Impact factor: 14.307
Authors: Michelle Kiebala; Jolanta Skalska; Carla Casulo; Paul S Brookes; Derick R Peterson; Shannon P Hilchey; Yun Dai; Steven Grant; Sanjay B Maggirwar; Steven H Bernstein Journal: Exp Hematol Date: 2014-10-22 Impact factor: 3.084
Authors: Rekha Rao; Srilatha Nalluri; Warren Fiskus; Ramesh Balusu; Atul Joshi; Uma Mudunuru; Kathleen M Buckley; Kelly Robbins; Celalettin Ustun; Gary W Reuther; Kapil N Bhalla Journal: Mol Cancer Ther Date: 2010-07-27 Impact factor: 6.261