NF-κB/STAT3/PI3K signaling crosstalk in iMycEμ B lymphoma

Molecular Cancer

Research

Hwakyung Yun¹  Siegfried Janz²  Seong-Su Han²  Dong-Ju Son²  Van S. Tompkins²  Eun-Sung Park³  Joong-Su Kim⁴  Seung-Tae Chung⁵  Liangping Peng⁶ 

[1] Department of Biological Sciences, Hanseo University, Choognam, South Korea;Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, USA;Department of Systems Biology, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA;Korea Research Institutes of Bioscience and Biotechnology, Daejeon, South Korea;National Institute of Toxicological Research, Korea Food and Dug Administration, Seoul, South Korea;The Public Health Research Institute Center, University of Medicine and Dentistry of New Jersey, Newark, NJ, USA;

关键词: Reverse Transcription Polymerase Chain Reaction;    Electrophoretic Mobility Shift Assay;    PI3K Signaling;    Signaling Crosstalk;    Spleen Masse;   

DOI  :  10.1186/1476-4598-9-97

 received in 2009-09-22, accepted in 2010-04-30,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundMyc is a well known driver of lymphomagenesis, and Myc-activating chromosomal translocation is the recognized hallmark of Burkitt lymphoma, an aggressive form of non-Hodgkin's lymphoma. We developed a model that mimics this translocation event by inserting a mouse Myc cDNA gene into the immunoglobulin heavy chain locus, just upstream of the intronic Eμ enhancer. These mice, designated iMycEμ, readily develop B-cell lymphoma. To study the mechanism of Myc-induced lymphoma, we analyzed signaling pathways in lymphoblastic B-cell lymphomas (LBLs) from iMycEμ mice, and an LBL-derived cell line, iMycEμ-1.ResultsNuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) were constitutively activated in iMycEμ mice, not only in LBLs but also in the splenic B-lymphocytes of young animals months before tumors developed. Moreover, inhibition of either transcription factor in iMycEμ-1 cells suppressed growth and caused apoptosis, and the abrogation of NF-κB activity reduced DNA binding by both STAT3 and Myc, as well as Myc expression. Inhibition of STAT3 signaling eliminated the activity of both NF-κB and Myc, and resulted in a corresponding decrease in the level of Myc. Thus, in iMycEμ-1 cells NF-κB and STAT3 are co-dependent and can both regulate Myc. Consistent with this, NF-κB and phosphorylated STAT3 were physically associated with one another. In addition, LBLs and iMycEμ-1 cells also showed constitutive AKT phosphorylation. Blocking AKT activation by inhibiting PI3K reduced iMycEμ-1 cell proliferation and caused apoptosis, via downregulation of NF-κB and STAT3 activity and a reduction of Myc levels. Co-treatment with NF-κB, STAT3 or/and PI3K inhibitors led to additive inhibition of iMycEμ-1 cell proliferation, suggesting that these signaling pathways converge.ConclusionsOur findings support the notion that constitutive activation of NF-κB and STAT3 depends on upstream signaling through PI3K, and that this activation is important for cell survival and proliferation, as well as for maintaining the level of Myc. Together, these data implicate crosstalk among NF-κB, STAT3 and PI3K in the development of iMycEμ B-cell lymphomas.

【 授权许可】

Unknown   
© Han et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.